Itraconazole analogs and use thereof

ABSTRACT

Provided herein are Itraconazole analogs. Also provided herein are methods of inhibition of Hedgehog pathway, vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, angiogenesis and treatment of disease with Itraconazole analogs.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 14/343,040 filed Apr. 10, 2014, now issued as U.S. Pat. No.9,346,791; which is a35 USC §371 National Stage application ofInternational Application No. PCT/US2012/054306 filed Sep. 7, 2012, nowexpired; which claims the benefit under 35 USC §119(e) to U.S.Application Ser. No. 61/531,819, now expired. The disclosure of each ofthe prior applications is considered part of and is incorporated byreference in the disclosure of this application.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under Grant No. CA122814awarded by the National Institutes of Health. The government has certainrights in the invention.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates generally to derivatives of Itraconazole and morespecifically to Itraconazole analogs and compositions as pharmaceuticalsfor the treatment of disease.

2. Background Information

Itraconazole is known for its use as a clinical agent for the treatmentof a broad spectrum of fungal infections. However, it has been shownthat Itraconazole also possesses potent in vitro and in vivoanti-angiogenic activity, and additionally inhibits both Hedgehog (Hh)signaling and the growth of murine medulloblastoma (MB) allografts withderegulated Hh activity. These observations have led to expansion of thepotential therapeutic application of Itraconazole and have even sparkedevaluation of this compound in four ongoing cancer clinical trials.

In an effort to better understand the structural parameters thatinfluence anti-angiogenic activity, all eight stereoisomers ofItraconazole (1a-1h, FIG. 1) have been synthesized and the individualstereoisomers evaluated for in vitro anti-angiogenic and 14α-demethylaseinhibition (14DM) dependent antifungal activities. The discrepancybetween the activities in one pair of trans-stereoisomers 1e-1f and theother stereoisomers suggests that the molecular mechanism ofItraconazole in anti-angiogenesis is distinct from that for antifungalactivity.

Although Itraconazole has demonstrated biological activity outside therealm of antifungal therapeutic regimens, little is known about thecorrelation between its pharmacological properties and structuralfeatures. The precise structural parameters of Itraconazole that areassociated with its biological activity (e.g., Hh inhibitory activity)have not yet been ascertained. Thus, a need exists to elucidate thestructure-activity relationship, for instance, in both anti-angiogenicand Hh targeting activity, and to exploit this knowledge in order toidentify analogs of Itraconazole with greater potency and/or decreasedside effects.

SUMMARY OF THE INVENTION

The present invention is based on the seminal discovery of arelationship between the Itraconazole side chain and putative bindingsite(s), which has been found to have an influence on its biologicalactivity.

Provided herein are compounds of structural Formula I, or an opticallypure stereoisomer or pharmaceutically acceptable salt thereof,

wherein:

X and Y are each independently CH or N;

A is CR⁶ or N;

B is CR⁷ or N;

W is CR⁸ or N;

V is CR⁹ or N;

Z is CR¹⁰ or N;

Q is O or CH₂;

R⁶, R⁷, R⁸, and R⁹ are each independently chosen from the groupconsisting of hydrogen, alkoxy, alkyl, amino, halogen, hydroxy,haloalkyl, perhaloalkyl, perhaloalkoxy, nitro, and cyano, any of whichmay be optionally substituted;

each R², R³, R⁴, and R⁵ are independently chosen from the groupconsisting of alkoxy, alkyl, amino, amido, halogen, hydroxy, haloalkyl,perhaloalkyl, perhaloalkoxy, nitro, and cyano, any of which may beoptionally substituted;

T is —OR¹¹ or hydrogen;

R¹¹ is hydrogen or substituted or unsubstituted alkyl;

G is —(CH₂)_(n) or G and R¹¹ together with the atom to which they areattached may optionally be joined together to form a monocyclicheterocycle including, but not limited to, dioxolane;

R¹ and R¹⁰ are each independently hydrogen or alkyl;

n is an integer between 0 and 2;

p and t are each independently an integer between 0 and 2;

q and m are each independently an integer between 0 and 4;

D is chosen from the group consisting of

wherein,

is a single or double bond;

U is O or S;

R¹² and R¹³ are each independently chosen from the group consisting ofhydrogen and alkyl, any of which may be optionally substituted; and

R¹⁴ is chosen from the group consisting of hydrogen, alkyl, arylalkyl,alkoxyalkyl, arylalkoxy, alkynylalkyl, alkylalkynylalkyl, alkenylalkyl,alkylalkenylalkyl, cycloalkyl, cyanoalkyl, cycloalkylalkyl, heteroalkyl,heterocycloalkyl, heteroaryl, heteroarylalkyl, andheterocycloalkylalkyl, any of which may be optionally substituted.

In certain aspects provided herein,

X and Z are each independently N;

Y is CH;

A is CR⁶;

B is CR⁷;

W is CR⁸;

V is CR⁹;

D is

p, t, and q are each independently 0;

m is 2; and

R¹, R⁶, R⁷, R⁸, and R⁹ are each independently hydrogen.

Also provided herein are compounds of structural Formula (II), or anoptically pure stereoisomer or pharmaceutically acceptable salt thereof,

In certain aspects, Q is CH₂. In one aspect, Q is O. In other aspects, Tis hydrogen. In yet other aspects, T is OR¹¹; and R¹¹ is hydrogen. Inone embodiment, Q is CH₂ and T is hydrogen. In another embodiment, Q isCH₂; T is OR¹¹; and R¹¹ is hydrogen. In yet another embodiment, Q is Oand T is hydrogen. In one embodiment, Q is O; T is OR¹¹; and R¹¹ ishydrogen.

In certain aspects, Q is O; n is 2; T is OR¹¹; and G and T are joinedtogether to form a dioxolane moiety:

Provided herein are compounds of structural Formula (III), or anoptically pure stereoisomer or pharmaceutically acceptable salt thereof,

In one aspect, R¹⁴ is chosen from the group consisting of hydrogen,alkyl, arylalkyl, alkoxyalkyl, arylalkoxy, alkynylalkyl, alkenylalkyl,cycloalkyl, cyanoalkyl, cycloalkylalkyl, and heterocycloalkylalkyl.

Provided herein are compounds of structural Formula (IV), or anoptically pure stereoisomer or pharmaceutically acceptable salt thereof,

In certain aspects, m is 2; and each R² is independently chlorine.

In other aspects, R¹⁴ is

In yet other aspects, W is CR⁸; and V is CR⁹. In certain aspects, p is0. In yet other aspects, each R⁴ is independently alkyl; and q is 0, 1,or 2. In further aspects, each R⁵ is independently halogen; and t is 0,1, or 2.

In one embodiment, W is CR⁸; V is CR⁹; p is 0; each R⁴ and R⁵ areindependently alkyl or halogen; and q and t are 0, 1, or 2. In anotherembodiment, W is CR⁸; V is CR⁹; p is 0; each R⁴ and R⁵ are independentlyalkyl or halogen; q and t are independently 0, 1, or 2; A is CR⁶ and Bis CR⁷ or N. In yet another embodiment, W is CR⁸; V is CR⁹; p is 0; eachR⁴ and R⁵ are independently alkyl or halogen; q and t are independently0, 1, or 2; A is N; and B is CR⁷.

In certain aspects, A is CR⁶; and B is CR⁷. In another aspect, t is 0.In other aspects, each R³ is independently halogen; and p is 0, 1, or 2.

In one embodiment, A is CR⁶; and B is CR⁷; t is 0; each R⁴ and R³ areindependently alkyl or halogen; and q and p are independently 0, 1, or2. In another embodiment, A is CR⁶; and B is CR⁷; t is 0; each R⁴ and R³are independently alkyl or halogen; q and p are independently 0, 1, or2; W is CR⁸ and V is CR⁹ or N. In yet another embodiment, A is CR⁶; B isCR⁷; t is 0; each R⁴ and R³ are independently alkyl or halogen; q and pare independently 0, 1, or 2; W is N; and V is CR⁹.

In certain embodiments, R⁶ is hydrogen. In other embodiments, R⁷ ishydrogen. In yet other embodiments, R⁸ is hydrogen. In furtherembodiments, R⁹ is hydrogen.

Also provided herein are compounds of structural Formula (V) or anoptically pure stereoisomer or pharmaceutically acceptable salt thereof,

In one aspect, X is CH; Y is CH; and Z is CR¹⁰. In certain aspects, X isN; Y is CH; and Z is CR¹⁰. In another aspect, X is CH; Y is CH; and Z isN. In yet another aspect, X is CH; Y is N; and Z is N. In certainembodiments, X, Y and Z are each independently N. In other embodiments,X is CH; Y is N; and Z is CR¹⁰. In further embodiments, X and Y are eachindependently N; and Z is CR¹⁰.

Provided herein are compounds of structural Formula (VI) or an opticallypure stereoisomer or pharmaceutically acceptable salt thereof,

In one aspect, m is 2; each R² is independently halogen, such aschlorine; and D is

Also provided herein, are compounds of structural Formula (VII) or anoptically pure stereoisomer or pharmaceutically acceptable salt thereof,

In certain aspects, m is 2; and R² is independently chosen from thegroup consisting of hydrogen, halogen, and perhaloalkyl.

In certain aspects, provided herein are compounds of Formula (VIII)

wherein R¹⁴ is straight chain or branched alkyl.

In other aspects, provided herein are compounds of Formula (VIII)wherein, when R¹⁴ is straight chain or branched alkyl, then R¹⁴ is notmethyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, or iso-pentyl.

In yet other aspects, provided herein are compounds of Formulae(I)-(VIII), wherein R¹⁴ is chosen from:

Certain embodiments also provide pharmaceutical compositions comprisingone or more compounds disclosed herein together with a pharmaceuticallyacceptable carrier, as well as methods of making and using the compoundsand compositions.

Provided herein are methods of inhibiting Hedgehog (Hh) pathway,comprising contacting a cell with a compound of structural Formula I,thereby inhibiting Hh pathway. Certain aspects provide for methods oftreating a Hh pathway-mediated disease, comprising administering atherapeutically effective amount of a compound of structural Formula (I)to a patient in need thereof.

Also provided herein are methods of inhibiting angiogenesis. The methodsinclude contacting a cell with a compound of structural Formula (I),thereby inhibiting angiogenesis. Also provided are methods for treatinga disease or disorder associated with angiogenesis, comprisingadministering to a subject in need thereof, a therapeutically effectiveamount of a compound of structural Formula (I).

The compounds disclosed herein may possess useful vascular endothelialgrowth factor receptor 2 (VEGFR2) inhibiting activity, and may be usedin the treatment or prophylaxis of a disease or condition in whichVEGFR2 plays an active role. In certain embodiments, VEGFR2glycosylation is inhibited by compounds of structural Formula (I). Inone aspect, methods for treating a VEGFR2-mediated disorder in a patientin need of such treatment, comprising administering to the patient atherapeutically effective amount of a compound or composition aredisclosed herein. In other aspects, the compounds disclosed herein maybe useful for treating fungal infection, either systemically ortopically.

As used herein, the terms below have the meanings indicated.

When ranges of values are disclosed, and the notation “from n1 . . . ton2” or “between n1 . . . and n2” is used, where n1 and n2 are thenumbers, then unless otherwise specified, this notation is intended toinclude the numbers themselves and the range between them. This rangemay be integral or continuous between and including the end values. Byway of example, the range “from 2 to 6 carbons” is intended to includetwo, three, four, five, and six carbons, since carbons come in integerunits. Compare, by way of example, the range “from 1 to 3 μM(micromolar),” which is intended to include 1 μM, 3 μM, and everythingin between to any number of significant figures (e.g., 1.255 μM, 2.1 μM,2.9999 μM, etc.). When n is set at 0 in the context of “0 carbon atoms”,it is intended to indicate a bond or null.

The term “about,” as used herein, is intended to qualify the numericalvalues which it modifies, denoting such a value as variable within amargin of error. When no particular margin of error, such as a standarddeviation to a mean value given in a chart or table of data, is recited,the term “about” should be understood to mean that range which wouldencompass the recited value and the range which would be included byrounding up or down to that figure as well, taking into accountsignificant figures.

The term “acyl,” as used herein, alone or in combination, refers to acarbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl,heterocycle, or any other moiety where the atom attached to the carbonylis carbon. An “acetyl” group refers to a —C(O)CH₃ group. An“alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached tothe parent molecular moiety through a carbonyl group. Examples of suchgroups include methylcarbonyl and ethylcarbonyl. Examples of acyl groupsinclude formyl, alkanoyl and aroyl.

The term “alkenyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain hydrocarbon group having one or moredouble bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkenyl will comprise from 2 to 6 carbon atoms. Theterm “alkenylene” refers to a carbon-carbon double bond system attachedat two or more positions such as ethenylene [(—CH═CH—), (—C::C—)].Examples of suitable alkenyl groups include ethenyl, propenyl,2-methylpropenyl, 1,4-butadienyl and the like. Unless otherwisespecified, the term “alkenyl” may include “alkenylene” groups.

The term “alkoxy,” as used herein, alone or in combination, refers to analkyl ether group, wherein the term alkyl is as defined below. Examplesof suitable alkyl ether groups include methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.

The term “alkyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain alkyl group containing from 1 to 20carbon atoms. In certain embodiments, said alkyl will comprise from 1 to10 carbon atoms. In further embodiments, said alkyl will comprise from 1to 6 carbon atoms. Alkyl groups may be optionally substituted as definedherein. Examples of alkyl groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,hexyl, octyl, noyl and the like. The term “alkylene,” as used herein,alone or in combination, refers to a saturated aliphatic group derivedfrom a straight or branched chain saturated hydrocarbon attached at twoor more positions, such as methylene (—CH₂—). Unless otherwisespecified, the term “alkyl” may include “alkylene” groups.

The term “alkylamino,” as used herein, alone or in combination, refersto an alkyl group attached to the parent molecular moiety through anamino group. Suitable alkylamino groups may be mono- or dialkylated,forming groups such as, for example, N-methylamino, N-ethylamino,N,N-dimethylamino, N,N-ethylmethylamino and the like.

The term “alkylidene,” as used herein, alone or in combination, refersto an alkenyl group in which one carbon atom of the carbon-carbon doublebond belongs to the moiety to which the alkenyl group is attached.

The term “alkylthio,” as used herein, alone or in combination, refers toan alkyl thioether (R—S—) group wherein the term alkyl is as definedabove and wherein the sulfur may be singly or doubly oxidized. Examplesof suitable alkyl thioether groups include methylthio, ethylthio,n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio,tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

The term “alkynyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain hydrocarbon group having one or moretriple bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkynyl comprises from 2 to 6 carbon atoms. In furtherembodiments, said alkynyl comprises from 2 to 4 carbon atoms. The term“alkynylene” refers to a carbon-carbon triple bond attached at twopositions such as ethynylene (—C:::C—, —C≡C—). Examples of alkynylgroups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl,butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like.Unless otherwise specified, the term “alkynyl” may include “alkynylene”groups.

The terms “amido” and “carbamoyl,” as used herein, alone or incombination, refer to an amino group as described below attached to theparent molecular moiety through a carbonyl group, or vice versa. Theterm “C amido” as used herein, alone or in combination, refers to aC(═O)NR₂ group with R as defined herein. The term “N amido” as usedherein, alone or in combination, refers to a RC(═O)NH group, with R asdefined herein. The term “acylamino” as used herein, alone or incombination, embraces an acyl group attached to the parent moietythrough an amino group. An example of an “acylamino” group isacetylamino (CH₃C(O)NH—).

The term “amino,” as used herein, alone or in combination, refers to—NRR′, wherein R and R′ are independently selected from the groupconsisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl,heteroaryl, and heterocycloalkyl, any of which may themselves beoptionally substituted. Additionally, R and R′ may combine to formheterocycloalkyl, either of which may be optionally substituted.

The term “aryl,” as used herein, alone or in combination, means acarbocyclic aromatic system containing one, two or three rings whereinsuch polycyclic ring systems are fused together. The term “aryl”embraces aromatic groups such as phenyl, naphthyl, anthracenyl, andphenanthryl.

The term “arylalkenyl” or “aralkenyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkenyl group.

The term “arylalkoxy” or “aralkoxy,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkoxy group.

The term “arylalkyl” or “aralkyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkyl group.

The term “arylalkynyl” or “aralkynyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkynyl group.

The term “arylalkanoyl” or “aralkanoyl” or “aroyl,” as used herein,alone or in combination, refers to an acyl group derived from anaryl-substituted alkanecarboxylic acid such as benzoyl, napthoyl,phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl,(2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

The term aryloxy as used herein, alone or in combination, refers to anaryl group attached to the parent molecular moiety through an oxy.

The terms “benzo” and “benz,” as used herein, alone or in combination,refer to the divalent group C6H4=derived from benzene. Examples includebenzothiophene and benzimidazole.

The term “carbamate,” as used herein, alone or in combination, refers toan ester of carbamic acid (—NHCOO—) which may be attached to the parentmolecular moiety from either the nitrogen or acid end, and which may beoptionally substituted as defined herein.

The term “O carbamyl” as used herein, alone or in combination, refers toa OC(O)NRR′ group with R and R′ as defined herein.

The term “N carbamyl” as used herein, alone or in combination, refers toa ROC(O)NR′ group, with R and R′ as defined herein.

The term “carbonyl,” as used herein, when alone includes formyl [—C(O)H]and in combination is a —C(O)— group.

The term “carboxyl” or “carboxy,” as used herein, refers to —C(O)OH orthe corresponding “carboxylate” anion, such as is in a carboxylic acidsalt. An “O carboxy” group refers to a RC(O)O— group, where R is asdefined herein. A “C carboxy” group refers to a —C(O)OR groups where Ris as defined herein.

The term “cyano,” as used herein, alone or in combination, refers to—CN.

The term “cycloalkyl,” or, alternatively, “carbocycle,” as used herein,alone or in combination, refers to a saturated or partially saturatedmonocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moietycontains from 3 to 12 carbon atom ring members and which may optionallybe a benzo fused ring system which is optionally substituted as definedherein. In certain embodiments, said cycloalkyl will comprise from 5 to7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronapthyl,indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and thelike. “Bicyclic” and “tricyclic” as used herein are intended to includeboth fused ring systems, such as decahydronaphthalene,octahydronaphthalene as well as the multicyclic (multicentered)saturated or partially unsaturated type. The latter type of isomer isexemplified in general by, bicyclo[1,1,1]pentane, camphor, adamantane,and bicyclo[3,2,1]octane.

The term “ester,” as used herein, alone or in combination, refers to acarboxy group bridging two moieties linked at carbon atoms.

The term “ether,” as used herein, alone or in combination, refers to anoxy group bridging two moieties linked at carbon atoms.

The term “halo,” or “halogen,” as used herein, alone or in combination,refers to fluorine, chlorine, bromine, or iodine.

The term “haloalkoxy,” as used herein, alone or in combination, refersto a haloalkyl group attached to the parent molecular moiety through anoxygen atom.

The term “haloalkyl,” as used herein, alone or in combination, refers toan alkyl group having the meaning as defined above wherein one or morehydrogens are replaced with a halogen. Specifically embraced aremonohaloalkyl, dihaloalkyl and polyhaloalkyl groups. A monohaloalkylgroup, for one example, may have an iodo, bromo, chloro or fluoro atomwithin the group. Dihalo and polyhaloalkyl groups may have two or moreof the same halo atoms or a combination of different halo groups.Examples of haloalkyl groups include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difiuorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. “Haloalkylene” refers to a haloalkyl group attached attwo or more positions. Examples include fluoromethylene.

(—CFH—), difluoromethylene (—CF₂—), chloromethylene (—CHCl—) and thelike.

The term “heteroalkyl,” as used herein, alone or in combination, refersto a stable straight or branched chain, or cyclic hydrocarbon group, orcombinations thereof, fully saturated or containing from 1 to 3 degreesof unsaturation, consisting of the stated number of carbon atoms andfrom one to three heteroatoms selected from the group consisting of O,N, and S, and wherein the nitrogen and sulfur atoms may optionally beoxidized and the nitrogen heteroatom may optionally be quaternized. Theheteroatom(s) O, N and S may be placed at any interior position of theheteroalkyl group. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃.

The term “heteroaryl,” as used herein, alone or in combination, refersto a 3 to 7 membered unsaturated heteromonocyclic ring, or a fusedmonocyclic, bicyclic, or tricyclic ring system in which at least one ofthe fused rings is aromatic, which contains at least one atom selectedfrom the group consisting of O, S, and N. In certain embodiments, saidheteroaryl will comprise from 5 to 7 carbon atoms. The term alsoembraces fused polycyclic groups wherein heterocyclic rings are fusedwith aryl rings, wherein heteroaryl rings are fused with otherheteroaryl rings, wherein heteroaryl rings are fused withheterocycloalkyl rings, or wherein heteroaryl rings are fused withcycloalkyl rings. Examples of heteroaryl groups include pyrrolyl,pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl,oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl,indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl,quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl,benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl,benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl,tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl,thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplarytricyclic heterocyclic groups include carbazolyl, benzidolyl,phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyland the like.

The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” asused herein, alone or in combination, each refer to a saturated,partially unsaturated, or fully unsaturated monocyclic, bicyclic, ortricyclic heterocyclic group containing at least one heteroatom as aring member, wherein each said heteroatom may be independently selectedfrom the group consisting of nitrogen, oxygen, and sulfur In certainembodiments, said hetercycloalkyl will comprise from 1 to 4 heteroatomsas ring members. In further embodiments, said hetercycloalkyl willcomprise from 1 to 2 heteroatoms as ring members. In certainembodiments, said hetercycloalkyl will comprise from 3 to 8 ring membersin each ring. In further embodiments, said hetercycloalkyl will comprisefrom 3 to 7 ring members in each ring. In yet further embodiments, saidhetercycloalkyl will comprise from 5 to 6 ring members in each ring.“Heterocycloalkyl” and “heterocycle” are intended to include sulfones,sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclicfused and benzo fused ring systems; additionally, both terms alsoinclude systems where a heterocycle ring is fused to an aryl group, asdefined herein, or an additional heterocycle group. Examples ofheterocycle groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl,dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl,dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl,benzothiazolyl, dihydroindolyl, dihy-dropyridinyl, 1,3-dioxanyl,1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl,pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and thelike. The heterocycle groups may be optionally substituted unlessspecifically prohibited.

The term “hydrazinyl” as used herein, alone or in combination, refers totwo amino groups joined by a single bond, i.e., —N—N—.

The term “hydroxy,” as used herein, alone or in combination, refers to—OH.

The term “hydroxyalkyl,” as used herein, alone or in combination, refersto a hydroxy group attached to the parent molecular moiety through analkyl group.

The term “imino,” as used herein, alone or in combination, refers to═N—.

The term “iminohydroxy,” as used herein, alone or in combination, refersto ═N(OH) and ═N—O—.

The phrase “in the main chain” refers to the longest contiguous oradjacent chain of carbon atoms starting at the point of attachment of agroup to the compounds of any one of the formulas disclosed herein.

The term “isocyanato” refers to a —NCO group.

The term “isothiocyanato” refers to a —NCS group.

The phrase “linear chain of atoms” refers to the longest straight chainof atoms independently selected from carbon, nitrogen, oxygen andsulfur.

The term “lower,” as used herein, alone or in a combination, where nototherwise specifically defined, means containing from 1 to and including6 carbon atoms.

The term “lower aryl,” as used herein, alone or in combination, meansphenyl or naphthyl, which may be optionally substituted as provided.

The term “lower heteroaryl,” as used herein, alone or in combination,means either: 1) monocyclic heteroaryl comprising five or six ringmembers, of which between one and four said members may be heteroatomsselected from the group consisting of O, S, and N; or 2) bicyclicheteroaryl, wherein each of the fused rings comprises five or six ringmembers, comprising between them one to four heteroatoms selected fromthe group consisting of O, S, and N.

The term “lower cycloalkyl,” as used herein, alone or in combination,means a monocyclic cycloalkyl having between three and six ring members.Lower cycloalkyls may be unsaturated. Examples of lower cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term “lower heterocycloalkyl,” as used herein, alone or incombination, means a monocyclic heterocycloalkyl having between threeand six ring members, of which between one and four may be heteroatomsselected from the group consisting of O, S, and N. Examples of lowerheterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl,piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyls maybe unsaturated.

The term “lower amino,” as used herein, alone or in combination, refersto —NRR′, wherein R and R′ are independently selected from the groupconsisting of hydrogen, lower alkyl, and lower heteroalkyl, any of whichmay be optionally substituted. Additionally, the R and R′ of a loweramino group may combine to form a five- or six-memberedheterocycloalkyl, either of which may be optionally substituted.

The term “mercaptyl” as used herein, alone or in combination, refers toan RS— group, where R is as defined herein.

The term “nitro,” as used herein, alone or in combination, refers to—NO₂.

The terms “oxy” or “oxa,” as used herein, alone or in combination, referto —O—.

The term “oxo,” as used herein, alone or in combination, refers to ═O.

The term “perhaloalkoxy” refers to an alkoxy group where all of thehydrogen atoms are replaced by halogen atoms.

The term “perhaloalkyl” as used herein, alone or in combination, refersto an alkyl group where all of the hydrogen atoms are replaced byhalogen atoms.

The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein,alone or in combination, refer to the —SO₃H group and its anion as thesulfonic acid is used in salt formation.

The term “sulfanyl,” as used herein, alone or in combination, refers to—S—.

The term “sulfinyl,” as used herein, alone or in combination, refers to—S(O)—.

The term “sulfonyl,” as used herein, alone or in combination, refers to—S(O)₂—.

The term “N sulfonamido” refers to a RS(═O)₂NR′ group with R and R′ asdefined herein.

The term “S sulfonamido” refers to a S(═O)₂NRR′, group, with R and R′ asdefined herein.

The terms “thia” and “thio,” as used herein, alone or in combination,refer to a —S— group or an ether wherein the oxygen is replaced withsulfur. The oxidized derivatives of the thio group, namely sulfinyl andsulfonyl, are included in the definition of thia and thio.

The term “thiol,” as used herein, alone or in combination, refers to an—SH group.

The term “thiocarbonyl,” as used herein, when alone includes thioformyl—C(S)H and in combination is a —C(S)— group.

The term “N thiocarbamyl” refers to an ROC(S)NR′— group, with R and R′as defined herein.

The term “O thiocarbamyl” refers to a —OC(S)NRR′, group with R and R′ asdefined herein.

The term “thiocyanato” refers to a —CNS group.

The term “trihalomethanesulfonamido” refers to a X₃CS(O)₂NR— group withX is a halogen and R as defined herein.

The term “trihalomethanesulfonyl” refers to a X₃CS(O)₂— group where X isa halogen.

The term “trihalomethoxy” refers to a X₃CO— group where X is a halogen.

The term “trisubstituted silyl,” as used herein, alone or incombination, refers to a silicone group substituted at its three freevalences with groups as listed herein under the definition ofsubstituted amino. Examples include trimethylsilyl,tert-butyldimethylsilyl, triphenylsilyl and the like.

Any definition herein may be used in combination with any otherdefinition to describe a composite structural group. By convention, thetrailing element of any such definition is that which attaches to theparent moiety. For example, the composite group alkylamido wouldrepresent an alkyl group attached to the parent molecule through anamido group, and the term alkoxyalkyl would represent an alkoxy groupattached to the parent molecule through an alkyl group.

When a group is defined to be “null,” what is meant is that said groupis absent.

The term “optionally substituted” means the anteceding group may besubstituted or unsubstituted. When substituted, the substituents of an“optionally substituted” group may include, without limitation, one ormore substituents independently selected from the following groups or aparticular designated set of groups, alone or in combination: loweralkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl,lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lowerhaloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl,phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, loweracyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester,lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, loweralkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lowerhaloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonicacid, trisubstituted silyl, N₃, SH, SCH₃, C(O)CH₃, CO₂CH₃, CO₂H,pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Twosubstituents may be joined together to form a fused five-, six-, orseven-membered carbocyclic or heterocyclic ring consisting of zero tothree heteroatoms, for example forming methylenedioxy or ethylenedioxy.An optionally substituted group may be unsubstituted (e.g., —CH₂CH₃),fully substituted (e.g., —CF₂CF₃), monosubstituted (e.g., —CH₂CH₂F) orsubstituted at a level anywhere in-between fully substituted andmonosubstituted (e.g., —CH₂CF₃). Where substituents are recited withoutqualification as to substitution, both substituted and unsubstitutedforms are encompassed. Where a substituent is qualified as“substituted,” the substituted form is specifically intended.Additionally, different sets of optional substituents to a particularmoiety may be defined as needed; in these cases, the optionalsubstitution will be as defined, often immediately following the phrase,“optionally substituted with.”

The term R or the term R′, appearing by itself and without a numberdesignation, unless otherwise defined, refers to a moiety selected fromthe group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl,heteroaryl and heterocycloalkyl, any of which may be optionallysubstituted. Such R and R′ groups should be understood to be optionallysubstituted as defined herein. Whether an R group has a numberdesignation or not, every R group, including R, R′ and R_(n) where n=(1,2, 3, . . . n), every substituent, and every term should be understoodto be independent of every other in terms of selection from a group.Should any variable, substituent, or term (e.g., aryl, heterocycle, R,etc.) occur more than one time in a formula or generic structure, itsdefinition at each occurrence is independent of the definition at everyother occurrence. Those of skill in the art will further recognize thatcertain groups may be attached to a parent molecule or may occupy aposition in a chain of elements from either end as written. Thus, by wayof example only, an unsymmetrical group such as —C(O)N(R)— may beattached to the parent moiety at either the carbon or the nitrogen.

Asymmetric centers exist in the compounds disclosed herein. Thesecenters are designated by the symbols “R” or “S,” depending on theconfiguration of substituents around the chiral carbon atom. It shouldbe understood that the invention encompasses all stereochemical isomericforms, including diastereomeric, enantiomeric, and epimeric forms, aswell as d-isomers and l-isomers, and mixtures thereof. Individualstereoisomers of compounds can be prepared synthetically fromcommercially available starting materials which contain chiral centersor by preparation of mixtures of enantiomeric products followed byseparation such as conversion to a mixture of diastereomers followed byseparation or recrystallization, chromatographic techniques, directseparation of enantiomers on chiral chromatographic columns, or anyother appropriate method known in the art. Starting compounds ofparticular stereochemistry are either commercially available or can bemade and resolved by techniques known in the art. Additionally, thecompounds disclosed herein may exist as geometric isomers. The presentinvention includes all cis, trans, syn, anti, entgegen (E), and zusammen(Z) isomers as well as the appropriate mixtures thereof. Additionally,compounds may exist as tautomers; all tautomeric isomers are provided bythis invention. Additionally, the compounds disclosed herein can existin unsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms.

The term “bond” refers to a covalent linkage between two atoms, or twomoieties when the atoms joined by the bond are considered to be part oflarger substructure. A bond may be single, double, or triple unlessotherwise specified. A dashed line between two atoms in a drawing of amolecule indicates that an additional bond may be present or absent atthat position.

The term “optically pure stereoisomer” refers to stereoisomeric, such asenantiomeric or diastereomeric excess or the absolute difference betweenthe mole fraction of each enantiomer or diastereomer.

The term “disease” as used herein is intended to be generallysynonymous, and is used interchangeably with, the terms “disorder” and“condition” (as in medical condition), in that all reflect an abnormalcondition of the human or animal body or of one of its parts thatimpairs normal functioning, is typically manifested by distinguishingsigns and symptoms, and causes the human or animal to have a reducedduration or quality of life.

The term “combination therapy” means the administration of two or moretherapeutic agents to treat a therapeutic condition or disorderdescribed in the present disclosure. Such administration encompassesco-administration of these therapeutic agents in a substantiallysimultaneous manner, such as in a single capsule having a fixed ratio ofactive ingredients or in multiple, separate capsules for each activeingredient. In addition, such administration also encompasses use ofeach type of therapeutic agent in a sequential manner. In either case,the treatment regimen will provide beneficial effects of the drugcombination in treating the conditions or disorders described herein.

The term “inhibition” (and by extension, “inhibitor”) as used hereinencompasses all forms of functional protein (enzyme, kinase, receptor,channel, etc., for example) inhibition, including neutral antagonism,inverse agonism, competitive inhibition, and non-competitive inhibition(such as allosteric inhibition). Inhibition may be phrased in terms ofan IC₅₀, defined below.

“Inhibitor” is used herein to refer to a compound that exhibits an IC₅₀activity with respect to its target of no more than about 100 μM andmore typically not more than about 50 μM, as measured in the assaysdescribed generally herein below. “IC₅₀” is that concentration ofinhibitor which reduces the activity of an enzyme to half-maximal level.Certain representative compounds of the present invention have beendiscovered to exhibit inhibition VEGFR2 or Hedgehog (Hh) pathway. Incertain embodiments, compounds will exhibit an IC₅₀ with respect toVEGFR2 or Hh pathway of no more than about 10 μM; in furtherembodiments, compounds will exhibit an IC₅₀ with respect to VEGFR2 or Hhpathway of no more than about 5 μM; in yet further embodiments,compounds will exhibit an IC₅₀ with respect VEGFR2 or Hh pathway of notmore than about 1 μM, as measured in the VEGFR2 or Hh pathway assaydescribed herein. In yet further embodiments, compounds will exhibit an1050 with respect to VEGFR2 or Hh pathway of not more than about 200 nM.

The phrase “therapeutically effective” is intended to qualify the amountof active ingredients used in the treatment of a disease or disorder.This amount will achieve the goal of reducing or eliminating the saiddisease or disorder.

The term “therapeutically acceptable” refers to those compounds (orsalts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitablefor use in contact with the tissues of patients without undue toxicity,irritation, and allergic response, are commensurate with a reasonablebenefit/risk ratio, and are effective for their intended use.

As used herein, reference to “treatment” of a patient is intended toinclude prophylaxis. The term “patient” means all mammals includinghumans. Examples of patients include humans, cows, dogs, cats, goats,sheep, pigs, and rabbits. Preferably, the patient is a human.

The term “prodrug” refers to a compound that is made more active invivo. Certain compounds disclosed herein may also exist as prodrugs, asdescribed in Hydrolysis in Drug and Prodrug Metabolism: Chemistry,Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M.Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compoundsdescribed herein are structurally modified forms of the compound thatreadily undergo chemical changes under physiological conditions toprovide the compound. Additionally, prodrugs can be converted to thecompound by chemical or biochemical methods in an ex vivo environment.For example, prodrugs can be slowly converted to a compound when placedin a transdermal patch reservoir with a suitable enzyme or chemicalreagent. Prodrugs are often useful because, in some situations, they maybe easier to administer than the compound, or parent drug. They may, forinstance, be bioavailable by oral administration whereas the parent drugis not. The prodrug may also have improved solubility in pharmaceuticalcompositions over the parent drug. A wide variety of prodrug derivativesare known in the art, such as those that rely on hydrolytic cleavage oroxidative activation of the prodrug. An example, without limitation, ofa prodrug would be a compound which is administered as an ester (the“prodrug”), but then is metabolically hydrolyzed to the carboxylic acid,the active entity. Additional examples include peptidyl derivatives of acompound.

The compounds disclosed herein can exist as therapeutically acceptablesalts. The present invention includes compounds listed above in the formof salts, including acid addition salts. Suitable salts include thoseformed with both organic and inorganic acids. Such acid addition saltswill normally be pharmaceutically acceptable. However, salts ofnon-pharmaceutically acceptable salts may be of utility in thepreparation and purification of the compound in question. Basic additionsalts may also be formed and be pharmaceutically acceptable. For a morecomplete discussion of the preparation and selection of salts, refer toPharmaceutical Salts: Properties, Selection, and Use (Stahl, P.Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

The term “therapeutically acceptable salt,” as used herein, representssalts or zwitterionic forms of the compounds disclosed herein which arewater or oil-soluble or dispersible and therapeutically acceptable asdefined herein. The salts can be prepared during the final isolation andpurification of the compounds or separately by reacting the appropriatecompound in the form of the free base with a suitable acid.Representative acid addition salts include acetate, adipate, alginate,L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate),bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate,formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate),lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate,methanesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,3-phenylproprionate, phosphonate, picrate, pivalate, propionate,pyroglutamate, succinate, sulfonate, tartrate, L-tartrate,trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate,para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groupsin the compounds disclosed herein can be quaternized with methyl, ethyl,propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl,dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and sterylchlorides, bromides, and iodides; and benzyl and phenethyl bromides.Examples of acids which can be employed to form therapeuticallyacceptable addition salts include inorganic acids such as hydrochloric,hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic,maleic, succinic, and citric. Salts can also be formed by coordinationof the compounds with an alkali metal or alkaline earth ion. Hence, thepresent invention contemplates sodium, potassium, magnesium, and calciumsalts of the compounds disclosed herein, and the like.

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reacting a carboxyl group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of therapeutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, and N,N′-dibenzylethylenediamine. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, andpiperazine.

While it may be possible for the compounds of the subject invention tobe administered as the raw chemical, it is also possible to present themas a pharmaceutical formulation. Accordingly, provided herein arepharmaceutical formulations which comprise one or more of certaincompounds disclosed herein, or one or more pharmaceutically acceptablesalts, esters, prodrugs, amides, or solvates thereof, together with oneor more pharmaceutically acceptable carriers thereof and optionally oneor more other therapeutic ingredients. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof. Properformulation is dependent upon the route of administration chosen. Any ofthe well-known techniques, carriers, and excipients may be used assuitable and as understood in the art; e.g., in Remington'sPharmaceutical Sciences. The pharmaceutical compositions disclosedherein may be manufactured in any manner known in the art, e.g., bymeans of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous, intraarticular,and intramedullary), intraperitoneal, transmucosal, transdermal, rectaland topical (including dermal, buccal, sublingual and intraocular)administration although the most suitable route may depend upon forexample the condition and disorder of the recipient. The formulationsmay conveniently be presented in unit dosage form and may be prepared byany of the methods well known in the art of pharmacy. Typically, thesemethods include the step of bringing into association a compound of thesubject invention or a pharmaceutically acceptable salt, ester, amide,prodrug or solvate thereof (“active ingredient”) with the carrier whichconstitutes one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation.

Formulations of the compounds disclosed herein suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. The active ingredient mayalso be presented as a bolus, electuary or paste.

Pharmaceutical preparations which can be used orally include tablets,push fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets may optionally becoated or scored and may be formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In addition, stabilizers may be added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. The formulations may be presentedin unit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in powder form or in a freeze-dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example, saline or sterile pyrogen-free water,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Formulations for parenteral administration include aqueous andnon-aqueous (oily) sterile injection solutions of the active compoundswhich may contain antioxidants, buffers, bacteriostats and solutes whichrender the formulation isotonic with the blood of the intendedrecipient; and aqueous and non-aqueous sterile suspensions which mayinclude suspending agents and thickening agents. Suitable lipophilicsolvents or vehicles include fatty oils such as sesame oil, or syntheticfatty acid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter, polyethylene glycol, or otherglycerides.

Certain compounds disclosed herein may be administered topically, thatis by non-systemic administration. This includes the application of acompound disclosed herein externally to the epidermis or the buccalcavity and the instillation of such a compound into the ear, eye andnose, such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral,intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin tothe site of inflammation such as gels, liniments, lotions, creams,ointments or pastes, and drops suitable for administration to the eye,ear or nose. The active ingredient for topical administration maycomprise, for example, from 0.001% to 10% w/w (by weight) of theformulation. In certain embodiments, the active ingredient may compriseas much as 10% w/w. In other embodiments, it may comprise less than 5%w/w. In certain embodiments, the active ingredient may comprise from 2%w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 1% w/wof the formulation.

Topical ophthalmic, otic, and nasal formulations of the presentinvention may comprise excipients in addition to the active ingredient.Excipients commonly used in such formulations include, but are notlimited to, tonicity agents, preservatives, chelating agents, bufferingagents, and surfactants. Other excipients comprise solubilizing agents,stabilizing agents, comfort-enhancing agents, polymers, emollients,pH-adjusting agents and/or lubricants. Any of a variety of excipientsmay be used in formulations of the present invention including water,mixtures of water and water-miscible solvents, such as C1-C7-alkanols,vegetable oils or mineral oils comprising from 0.5 to 5% non-toxicwater-soluble polymers, natural products, such as alginates, pectins,tragacanth, karaya gum, guar gum, xanthan gum, carrageenin, agar andacacia, starch derivatives, such as starch acetate and hydroxypropylstarch, and also other synthetic products such as polyvinyl alcohol,polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide,preferably cross-linked polyacrylic acid and mixtures of those products.The concentration of the excipient is, typically, from 1 to 100,000times the concentration of the active ingredient. In preferredembodiments, the excipients to be included in the formulations aretypically selected on the basis of their inertness towards the activeingredient component of the formulations.

Relative to ophthalmic, otic, and nasal formulations, suitabletonicity-adjusting agents include, but are not limited to, mannitol,sodium chloride, glycerin, sorbitol and the like. Suitable bufferingagents include, but are not limited to, phosphates, borates, acetatesand the like. Suitable surfactants include, but are not limited to,ionic and nonionic surfactants (though nonionic surfactants arepreferred), RLM 100, POE 20 cetylstearyl ethers such as Procol® CS20 andpoloxamers such as Pluronic® F68.

The formulations set forth herein may comprise one or morepreservatives. Examples of such preservatives include p-hydroxybenzoicacid ester, sodium perborate, sodium chlorite, alcohols such aschlorobutanol, benzyl alcohol or phenyl ethanol, guanidine derivativessuch as polyhexamethylene biguanide, sodium perborate,polyquarternium-1, amino alcohols such as AMP-95, or sorbic acid. Incertain embodiments, the formulation may be self-preserved so that nopreservation agent is required.

For ophthalmic, otic, or nasal administration, the formulation may be asolution, a suspension, or a gel. In preferred aspects, the formulationsare for topical application to the eye, nose, or ear in aqueous solutionin the form of drops. The term “aqueous” typically denotes an aqueousformulation wherein the formulation is >50%, more preferably >75% and inparticular >90% by weight water. These drops may be delivered from asingle dose ampoule which may preferably be sterile and thus renderbacteriostatic components of the formulation unnecessary. Alternatively,the drops may be delivered from a multi-dose bottle which may preferablycomprise a device which extracts any preservative from the formulationas it is delivered, such devices being known in the art.

For ophthalmic disorders, components of the invention may be deliveredto the eye as a concentrated gel or a similar vehicle, or as dissolvableinserts that are placed beneath the eyelids.

The formulations of the present invention that are adapted for topicaladministration to the eye are preferably isotonic, or slightly hypotonicin order to combat any hypertonicity of tears caused by evaporationand/or disease. This may require a tonicity agent to bring theosmolality of the formulation to a level at or near 210-320 milliosmolesper kilogram (mOsm/kg). The formulations of the present inventiongenerally have an osmolality in the range of 220-320 mOsm/kg, andpreferably have an osmolality in the range of 235-300 mOsm/kg. Theophthalmic formulations will generally be formulated as sterile aqueoussolutions.

In certain ophthalmic embodiments, the compositions of the presentinvention are formulated with one or more tear substitutes. A variety oftear substitutes are known in the art and include, but are not limitedto: monomeric polyols, such as, glycerol, propylene glycol, and ethyleneglycol; polymeric polyols such as polyethylene glycol; cellulose esterssuch hydroxypropylmethyl cellulose, carboxy methylcellulose sodium andhydroxy propylcellulose; dextrans such as dextran 70; vinyl polymers,such as polyvinyl alcohol; and carbomers, such as carbomer 934P,carbomer 941, carbomer 940 and carbomer 974P. Certain formulations ofthe present invention may be used with contact lenses or otherophthalmic products.

Preferred formulations are prepared using a buffering system thatmaintains the formulation at a pH of about 4.5 to a pH of about 8. Amost preferred formulation pH is from 6 to 8.

In particular embodiments, a formulation of the present invention isadministered once a day. However, the formulations may also beformulated for administration at any frequency of administration,including once a week, once every 5 days, once every 3 days, once every2 days, twice a day, three times a day, four times a day, five times aday, six times a day, eight times a day, every hour, or any greaterfrequency. Such dosing frequency is also maintained for a varyingduration of time depending on the therapeutic regimen. The duration of aparticular therapeutic regimen may vary from one-time dosing to aregimen that extends for months or years. The formulations areadministered at varying dosages, but typical dosages are one to twodrops at each administration, or a comparable amount of a gel or otherformulation. One of ordinary skill in the art would be familiar withdetermining a therapeutic regimen for a specific indication.

Gels for topical or transdermal administration may comprise, generally,a mixture of volatile solvents, nonvolatile solvents, and water. Incertain embodiments, the volatile solvent component of the bufferedsolvent system may include lower (C₁-C₆) alkyl alcohols, lower alkylglycols and lower glycol polymers. In further embodiments, the volatilesolvent is ethanol. The volatile solvent component is thought to act asa penetration enhancer, while also producing a cooling effect on theskin as it evaporates. The nonvolatile solvent portion of the bufferedsolvent system is selected from lower alkylene glycols and lower glycolpolymers. In certain embodiments, propylene glycol is used. Thenonvolatile solvent slows the evaporation of the volatile solvent andreduces the vapor pressure of the buffered solvent system. The amount ofthis nonvolatile solvent component, as with the volatile solvent, isdetermined by the pharmaceutical compound or drug being used. When toolittle of the nonvolatile solvent is in the system, the pharmaceuticalcompound may crystallize due to evaporation of volatile solvent, whilean excess may result in a lack of bioavailability due to poor release ofdrug from solvent mixture. The buffer component of the buffered solventsystem may be selected from any buffer commonly used in the art; incertain embodiments, water is used. A common ratio of ingredients isabout 20% of the nonvolatile solvent, about 40% of the volatile solvent,and about 40% water. There are several optional ingredients which can beadded to the topical composition. These include, but are not limited to,chelators and gelling agents. Appropriate gelling agents can include,but are not limited to, semisynthetic cellulose derivatives (such ashydroxypropylmethylcellulose), synthetic polymers, galactomannanpolymers (such as guar and derivatives thereof) and cosmetic agents.

Lotions include those suitable for application to the skin or eye. Aneye lotion may comprise a sterile aqueous solution optionally containinga bactericide and may be prepared by methods similar to those for thepreparation of drops. Lotions or liniments for application to the skinmay also include an agent to hasten drying and to cool the skin, such asan alcohol or acetone, and/or a moisturizer such as glycerol or an oilsuch as castor oil or arachis oil.

Creams, ointments or pastes are semi-solid formulations of the activeingredient for external application. They may be made by mixing theactive ingredient in finely-divided or powdered form, alone or insolution or suspension in an aqueous or non-aqueous fluid, with the aidof suitable machinery, with a greasy or non-greasy base. The base maycomprise hydrocarbons such as hard, soft or liquid paraffin, glycerol,beeswax, a metallic soap; a mucilage; an oil of natural origin such asalmond, corn, arachis, castor or olive oil; wool fat or its derivativesor a fatty acid such as steric or oleic acid together with an alcoholsuch as propylene glycol or a macrogel. The formulation may incorporateany suitable surface active agent such as an anionic, cationic ornon-ionic surfactant such as a sorbitan ester or a polyoxyethylenederivative thereof. Suspending agents such as natural gums, cellulosederivatives or inorganic materials such as silicaceous silicas, andother ingredients such as lanolin, may also be included.

Drops may comprise sterile aqueous or oily solutions or suspensions andmay be prepared by dissolving the active ingredient in a suitableaqueous solution of a bactericidal and/or fungicidal agent and/or anyother suitable preservative, and, in certain embodiments, including asurface active agent. The resulting solution may then be clarified byfiltration, transferred to a suitable container which is then sealed andsterilized by autoclaving or maintaining at 98-100° C. for half an hour.Alternatively, the solution may be sterilized by filtration andtransferred to the container by an aseptic technique. Examples ofbactericidal and fungicidal agents suitable for inclusion in the dropsare phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride(0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for thepreparation of an oily solution include glycerol, diluted alcohol andpropylene glycol.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavored basis such as sucrose and acacia or tragacanth,and pastilles comprising the active ingredient in a basis such asgelatin and glycerin or sucrose and acacia.

For administration by inhalation, compounds may be convenientlydelivered from an insufflator, nebulizer pressurized packs or otherconvenient means of delivering an aerosol spray. Pressurized packs maycomprise a suitable propellant such as dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Alternatively, for administration by inhalation or insufflation, thecompounds according to the invention may take the form of a dry powdercomposition, for example a powder mix of the compound and a suitablepowder base such as lactose or starch. The powder composition may bepresented in unit dosage form, in for example, capsules, cartridges,gelatin or blister packs from which the powder may be administered withthe aid of an inhalator or insufflator.

Preferred unit dosage formulations are those containing an effectivedose, as herein below recited, or an appropriate fraction thereof, ofthe active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations described above may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

Compounds may be administered orally or via injection at a dose of from0.1 to 500 mg/kg per day. The dose range for adult humans is generallyfrom 5 mg to 2 g/day. Tablets or other forms of presentation provided indiscrete units may conveniently contain an amount of one or morecompounds which is effective at such dosage or as a multiple of thesame, for instance, units containing 5 mg to 500 mg, usually around 10mg to 200 mg.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

The compounds can be administered in various modes, e.g., orally,topically, or by injection. The precise amount of compound administeredto a patient will be the responsibility of the attendant physician. Thespecific dose level for any particular patient will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, general health, sex, diets, time ofadministration, route of administration, rate of excretion, drugcombination, the precise disorder being treated, and the severity of theindication or condition being treated. Also, the route of administrationmay vary depending on the condition and its severity.

In certain instances, it may be appropriate to administer at least oneof the compounds described herein (or a pharmaceutically acceptablesalt, ester, or prodrug thereof) in combination with another therapeuticagent. By way of example only, if one of the side effects experienced bya patient upon receiving one of the compounds herein is hypertension,then it may be appropriate to administer an anti-hypertensive agent incombination with the initial therapeutic agent. Or, by way of exampleonly, the therapeutic effectiveness of one of the compounds describedherein may be enhanced by administration of an adjuvant (i.e., by itselfthe adjuvant may only have minimal therapeutic benefit, but incombination with another therapeutic agent, the overall therapeuticbenefit to the patient is enhanced). Or, by way of example only, thebenefit of experienced by a patient may be increased by administeringone of the compounds described herein with another therapeutic agent(which also includes a therapeutic regimen) that also has therapeuticbenefit. By way of example only, in a treatment for diabetes involvingadministration of one of the compounds described herein, increasedtherapeutic benefit may result by also providing the patient withanother therapeutic agent for diabetes. In any case, regardless of thedisease, disorder or condition being treated, the overall benefitexperienced by the patient may simply be additive of the two therapeuticagents or the patient may experience a synergistic benefit.

In any case, the multiple therapeutic agents (at least one of which is acompound disclosed herein) may be administered in any order or evensimultaneously. If simultaneously, the multiple therapeutic agents maybe provided in a single, unified form, or in multiple forms (by way ofexample only, either as a single pill or as two separate pills). One ofthe therapeutic agents may be given in multiple doses, or both may begiven as multiple doses. If not simultaneous, the timing between themultiple doses may be any duration of time ranging from a few minutes tofour weeks.

Thus, in another aspect, certain embodiments provide methods fortreating Rho kinase-mediated disorders in a human or animal subject inneed of such treatment comprising administering to said subject anamount of a compound disclosed herein effective to reduce or preventsaid disorder in the subject in combination with at least one additionalagent for the treatment of said disorder that is known in the art. In arelated aspect, certain embodiments provide therapeutic compositionscomprising at least one compound of disclosed herein in combination withone or more additional agents for the treatment of Rho kinase-mediateddisorders.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the structures of the eight Itraconazole diastereomersarising from three stereogenic centers numbered 2, 4, and 2′. Thecis-designation denotes that the two substituents in the boxes are onthe same side of the 1,3-dioxolane ring, while trans-denotes theopposite orientation.

FIG. 2 shows the structures of terconazole (A) and ketoconazole (B).

FIG. 3 is a bar graph that depicts how the number of carbons andbranching of the Itraconazole side chain influence the degree ofglycosylation inhibition.

FIG. 4 is a scatter plot showing the correlation between potency in MBand HUVEC proliferation.

FIG. 5 is a bar graph that shows length, branching and polarity ofItraconazole side chain influences Hh pathway inhibition.

FIG. 6 is a schematic representation of the VEGFR2 glycosylation scoringsystem.

FIG. 7 is a graph that shows the correlation between MB proliferationpotency and Hh pathway inhibition. Box=interquartile range,Wiskers=adjacent values, Bars=median, Diamond=mean, Circles=data points,p-value=0.05 as determined by Cuzick test for trend.

FIG. 8 is a graph showing discordance between VEGFR2 glycosylation inHUVEC and Hh pathway inhibition in MB cells. bars=median±interquartilerange.

FIGS. 9A-9C are graphic representations of validation andcharacterization by Smo inhibitor activity on proliferation and Hhpathway activation and enrichment of CD15 expressing cells in MBcultures. FIG. 9A. Dose-dependent inhibition of MB proliferation byHhAntag (▪), GDC-0449 (□), and Itraconazole (•). FIG. 9B. Dose-dependentinhibition of Gli1 transcript levels by HhAntag (▪), GDC-0449 (▪), andItraconazole (□) in established MB cultures is coupled to inhibition ofMB proliferation. FIG. 9C. Flow cytometric analysis of CD 15 expressionin MB cultures; white=isotype control, black=α-CD15.

FIG. 10 is a table of the IC₉₀ values for MB proliferation assay andassociated Gli1 transcript levels.

DETAILED DESCRIPTION OF THE INVENTION

Itraconazole shares a large degree of structural similarity with theother azole antifungals, such as terconazole and ketoconazole (FIGS. 1and 2), which, despite their equipotent antifungal activity incomparison to Iitraconazole, do not inhibit proliferation of humanumbilical vein endothelial cells (HUVEC) and fail to induce the VEGFR2glycosylation defect (data not shown). The structural differences areparticularly evident with respect to the triazolone ring and itssec-butyl side chain. This is suggestive that these moieties may beassociated with the unique activities of Itraconazole. Thus, a libraryof twenty-five itraconazole analogs has been synthesized in which thesec-butyl side chain was replaced by a group of substituents withdiverse structural variations. These analogs were evaluated in severalassays, including HUVEC proliferation, VEGFR2 glycosylation,medulloblastoma (MB) proliferation, and Hh signaling as measured by Gli1transcript levels as a pharmacodynamic marker of pathway activation.

Studies designed to investigate the molecular basis of theanti-angiogenic activity of itraconazole have revealed several cellularand biochemical effects in HUVEC. Itraconazole inhibits cholesteroltrafficking in late endosomes/lysosomes and blocks mTORC1 and mTORC2signaling. More recently, Itraconazole has been shown to impede thematuration of N-linked sugars appended to vascular endothelial growthfactor receptor 2 (VEGFR2) and block VEGF-activated phosphorylation ofthe receptor, thereby arresting downstream signaling. Despite these newmechanistic insights, however, the direct target(s) of Itraconazoleremains unknown; therefore, the preparation and analysis of thebiological activity of a variety of Itraconazole analogs was undertaken.

The synthetic route for the syntheses of Itraconazole analogs 7a-7n(Table 1) with linear, branched, or cyclic hydrocarbon side chains isshown in Scheme 1. Because the 2S,4R-cis-stereochemistry on the1,3-dioxolane ring is most favored for antiangiogenic activity, (unlessotherwise stated) one single diastereomer 6a was used as the startingmaterial to make the analogs.

TABLE 1 Side Chain Structures of Compounds 4a-4n, 5a-5n, and 7a-7nCompounds R 4a/5a/7a

4b/5b/7b

4c/5c/7c

4d/5d/7d

4e/5e/7e

4f/5f/7f

4g/5g/7g

4h/5h/7h^(a)

4i/5i/7i

4j/5j/7j

4k/5k/7k

4l/5l/7l

4m/5m/7m

4n/5n/7n

^(a)Racemic on the side chain.

Alkylated compounds 4a-4n (Table 1) were prepared by reaction of thefree triazolone precursor 2 with commercially available alkyl bromidesor alkyl tosylates synthesized from commercially available alcohols. Foralkyl bromides or tosylates with a low boiling point, or potentially lowstability or high reactivity at high temperatures, the reactions werecarried out at room temperature with potassium carbonate and 18-crown-6.De-methylation of 4a-4n with concentrated aqueous hydrobromic acid at110° C. afforded the corresponding phenols 5a-5n (Table 1) in excellentyields. Final coupling of 5a-5n with 1,3-dioxolane tosylate 6a gave thedesired side chain analogs 7a-7n.

The analogs 7o-7q (Table 2) were prepared according to the syntheticroute shown in Scheme 2. To incorporate the functional groups (azido,internal alkyne, and benzophenone) into the side chain, the methylprotecting group of the phenolic hydroxyl group was replaced with themethoxymethyl (MOM) group to avoid the harsh demethylation conditions(HBr, 110° C.). To start with,N-(4-hydroxyphenyl)-N′-(4-nitrophenyl)-piperazine 10 was prepared byheating the mixture of commercially availableN-(4-hydroxylphenyl)-piperazine 8 and 1-chloro-4-nitrobenzene 9 inN-methylpyrrolidone (NMP) overnight. The crude product, isolated fromisopropanol precipitation, was directly reacted with methoxymethylchloride to afford the MOM-protected intermediate 11, which was purifiedby column chromatography. Subsequently, the nitro group in 11 wasreduced to the amino group by refluxing with hydrazine monohydrate inthe presence of 10% palladium on charcoal. In a three-step sequence, theaniline intermediate 12 was then reacted with phenyl chloroformate,hydrazine monohydrate, and formamidine acetate to construct thetriazolone ring in 51% yield over three steps. Next, the N-alkylation of13 with the corresponding alkylating reagents 3o-3q (see Examples) underbasic conditions afforded the intermediates 14a-14c (Table 2), whichwere in turn treated with 50% trifluoroacetic acid in dichloromethane atroom temperature to remove the MOM group. The acquired phenols 5o-5qwere subjected to the aforementioned coupling conditions to give thefinal products 7o-7q.

TABLE 2 Side Chain Structures of Compounds 14a-14c, 5o-5q, and 7o-7qCompounds Structure of the R group 14a/5o/7o

14b/5p/7p

14c/5q/7q

Although the synthetic route described in Scheme 2 can accommodate abroad range of functional groups, two column purifications were usuallyrequired to remove DMSO and obtain the final products in good quality.To avoid the use of DMSO as the reaction solvent, a linear syntheticmethodology, as shown in Scheme 3, was adopted. The reaction sequencewas first examined by using 2R, 4R-cis-tosylate 6b as the startingmaterial due to its relatively high abundance and similar biologicalactivity according to the reported stereoisomers.³N-(4-hydroxyphenyl)-N′-(4-nitrophenyl)-piperazine 10 was purified bycolumn chromatography before it was coupled with 6b. Formation of thetriazolone moiety in 17b from the nitro group in 15b was achieved byfollowing the similar reaction conditions described in Scheme 2. Usingpotassium carbonate in combination with 18-crown-6 as the deprotonationreagents, the final N-alkylation of 17b with 4-pentynyl-1-tosylate 3swas performed in acetonitrile at 40° C. to give the final product 7r in63% yield. Analogs 7s-7x (Table 3) were obtained from 2S,4S-cis-tosylate 6a and the corresponding alkyl bromides or tosylates3s-3x in a similar fashion.

The activity of the analogs against HUVEC proliferation, an in vitroproxy for angiogenesis inhibition (Table 3) was analyzed. From Table 3,it is clear that modification of the side chain in most analogs did notdramatically affect the activity. Those analogs with extremely shortside chains (7a and 7b) or lacking any side chain (17a) had lowerpotency for inhibition of HUVEC proliferation than Itraconazole. A fewanalogs, however, possessed considerably higher potency, including 7rand 7u.

TABLE 3 Inhibition of HUVEC Proliferation and VEGFR2 Glycosylation, MBProliferation and Gli1 Transcription by Itraconazole Stereoisomers 1a-1hand Side Chain Analogs 17a and 7a-7x^(a)

Gli1 Proliferation Glycosylation MB Inhibition (IC₅₀/ (2 μMProliferation (IC₉₀ Compounds R IC₅₀ Itra) dose) (IC₅₀/IC₅₀ Itra)Prolif. dose) 1a 2S,4R,2′S

0.8^(b) ++ 1.3 nd 1b 2S,4R,2′R

1.1^(b) ++ 1.4 nd 1c 2R,4S,2′S

1.6^(b) ++ 1.3 nd 1d 2R,4S,2′R

2.5^(b) ++ 1.7 nd 1e 2S,4S,2′S

3.1^(b) + 2.1 nd 1f 2S,4S,2′R

3.9^(b) − 1.7 nd 1g 2R,4R,2′S

3.2^(b) + 1.5 nd 1h 2R,4R,2′R

3.7^(b) − 2.3 nd 17a^(c,d) H 2.78 − 0.89 ++ 7a^(d)

4.00 − 2.71 − 7b^(d)

2.94 − 1.62 − 7c^(d)

1.06 + 1.01 ++ 7d^(d)

2.18 − 1.06 − 7e^(d)

2.10 − 0.70 − Itra^(f)

1.00 ++ 1.00 ++ 7f^(d)

1.32 ++ 0.86 − 7g

1.09 − 0.66 ++ 7h^(e)

0.75 ++ 0.38 ++ 7i^(d)

1.42 + 0.41 ++ 7j

1.10 + 0.54 ++ 7k

0.44 ++ 0.37 − 7l

0.50 ++ 0.50 + 7m

2.24^(g) − 0.67 ++ 7n

1.45^(g) − 0.69 ++ 7o

1.09 − 1.07 ++ 7p

0.30 + 0.70 + 7q

>69.9^(g) − 0.80 − 7r^(a)

0.14 − 0.71 ++ 7s

1.57 − 0.63 ++ 7t

0.73 − 0.94 ++ 7u

0.18 ++ 0.84 + 7v

0.77 ++ 0.74 + 7w

>13.8 + 1.32 + 7x

1.1^(g) − 1.18 − ^(a)Stereochemistry on the 1,3-dioxolane ring is 2S,4Rfor 17a, 7a-7q, and 7s-7x and 2R,4S for 7r; ^(b)Proliferation data fromref. 3; ^(c)Purity is 94.0%, t_(R) = 6.92 min; ^(d)Already reported inRef. 7; ^(e)Mixture of the four cis-diastereomers, from Sigma-Aldrich;^(f)Mixture of stereoisomers on the side chain; ^(g)EC₅₀/IC₅₀ Itra.

The similar or even improved potency for compounds 7k, 7l and 7v, all ofwhich have bulky side chains, suggests a putative binding site that isnot sterically hindered. The relatively rigid conformation in 7o, 7s,and 7t further supports this idea and further suggests that the bindingpocket in the putative target may be quite deep; however, the loss ofactivity in 7w does not appear to be consistent with this trend. Onepossible explanation for this observation is that the loss oflipophilicity resulting from the incorporation of two nitrogens may haveaffected activity. This may be supported by the data for 7x in which anincrease in lipophilicity appears to have compensated for the presenceof the diazirine. The near total loss of activity in 7q may beindicative of a limit to the size of the side chain with respect toinhibition of HUVEC proliferation.

Perhaps most notably, the potency of Itraconazole against HUVECproliferation was significantly increased by the incorporation ofrelatively small functional groups, such as the azido group in 7p, theterminal alkyne in 7r, and the cyano group in 7u. This implies thatthere are some interactions in the binding site of the side chain thatare not utilized by the sec-butyl group in Itraconazole. These resultsalso suggest that substituents in place of the sec-butyl group ofItraconazole can be further explored to optimize the potency ofItraconazole.

Because Itraconazole was found to block the normal maturation ofN-glycans on VEGFR2, the influence of the side chain structure on thisactivity was analyzed as well (Table 3). VEGFR2 hypoglycosylation wasscored either robust (++), intermediate (+), or absent (−) (FIG. 6).Robust inhibitors of glycosylation had significantly (p<0.05) greaterpotencies against proliferation than the group in which thehypoglycosylation was absent, suggesting that this phenotype makes anoverall contribution to inhibition of HUVEC proliferation (Table 4).Side chains comprised of 4 carbons or greater with branching at the α orβ position appeared to strongly favor robust glycosylation inhibitioncompared with all other structural isomers (FIG. 3). However, compound7j produced an intermediate glycosylation defect and was an exception tothis observation. Compared with 7k, 7l, and 7v, the other analogs, whichcontained bulky side chains and retained glycosylation inhibition, 7jhad the greatest number of possible rotational isomers, suggesting thatonly certain conformations may be suitable for glycosylation inhibition.

TABLE 4 Correlation between HUVEC Proliferation Inhibition andGlycosylation Phenotype Glycosylation Inhibition − + ++ n 10 7 16 MeanIC₅₀ ^(a) (μM) 6.3 3.4 1.0 Mean Log2 (IC₅₀ ^(a)) 1.0 0.9 −0.32p-value^(b, c) N/A 0.83 0.04 ^(a)Relative to Itraconazole (IC₅₀analog/IC₅₀ itraconazole); ^(b)p-value calculated by a two-tailedStudent's t-test from log transformed data; ^(c)compared to the “−”group.

Itraconazole has recently found to inhibit Hh pathway signaling in a 3T3cell-based reporter system and in medulloblastoma allografts exhibitingHh pathway-dependent growth. This activity against Hh signaling alsoseems to be unrelated to inhibition of 14DM, as other azole antifungalagents demonstrate decreased potency against this pathway, regardless oftheir activity on human 14DM. To explore the relation of theanti-angiogenic and anti-Hh signaling capacity of Itraconazole, theanti-proliferative potency of the side chain analogs in MB cultures wasassessed. These cultures were derived from Ptch^(−/+);p53^(−/−) micethat spontaneously develop medulloblastoma associated with ligandindependent Hh pathway activation. IC₅₀ values for proliferation weredetermined for analogs and are represented as relative potenciescompared to that of Itraconazole (Table 3). Overall, there was poorcorrelation between analog potency ratios for MB and HUVEC proliferation(Spearman r=0.327; p=0.063) (FIG. 4). Notably, compounds 7q and 7w,which lost >69.9- and >13.8-fold of activity against HUVEC,respectively, had respective relative activities of 0.8 and 1.32 againstMB proliferation when compared to Itraconazole. Furthermore, the lack ofdata points in the lower right quadrant of FIG. 4 illustrates thatwithout exception, all analogs demonstrating equivalent or increasedpotency against HUVEC proliferation with respect to Itraconazole alsodemonstrate equivalent or increased potency against MB proliferation.These findings are consistent with the possibility that the target ofItraconazole in HUVEC may also contribute to the potency of Itraconazoleagainst MB proliferation.

Inhibitors of the Hh pathway are known to inhibit MB cell proliferation.However, MB cell proliferation is also affected by drugs with targetsother than Hh signaling. Therefore, to determine the extent to which thedemonstrated potencies on MB proliferation are associated with Hhpathway inhibition, established MB colonies were exposed to theItraconazole analogs at the IC₉₀ for MB proliferation and quantifiedtranscript levels of Gli1, a transcriptional gene target of the Hhpathway. These data were then scored based on transcript levelsassociated with exposure of MB to synthetic Smoothened inhibitors, HhAntag and GDC-0449 (vismogedib) at the IC₉₀ for proliferation. Theresults are listed in Table 3.

Overall, there was a statistically significant association betweeninhibition of MB proliferation and inhibition of Hh pathway activity(p=0.05; FIG. 7). However, some analogs with relatively weak inhibitionof Gli1 expression demonstrated potent inhibition of MB proliferation,suggesting that in these instances, anti-proliferative activity waspredominantly Hh pathway independent.

There was no evident association between inhibition of VEGFR2glycosylation and targeting of the Hh pathway (FIG. 8). Nine of tenanalogs demonstrating strong inhibition of the Hh pathway did notinhibit VEGFR2 glycosylation. Furthermore, of the six strongestinhibitors of VEGFR2 glycosylation, two were not associated withHh-dependent inhibition, three were intermediate inhibitors, and onlyone strongly inhibited Hh signaling Notably, with the exception ofcompound 7h, all analogs demonstrating strong inhibition of VEGFR2glycosylation also demonstrated increased potency against MBproliferation. These findings reveal a high level of discordance betweenthese pharmacodynamic markers.

A study of side chain modifications associated with strong Hh pathwayinhibition reveals several structure-activity relationship (SAR) trends.Analogs with side chains of three carbons or more in length withoutpolar groups or branching at the β carbon demonstrated strong inhibitionof Hh pathway activity (FIG. 5). Compound 7e is an exception, as it wasnot associated with strong Hh pathway inhibition, yet structurallyclosely related analogs 7c and 7g exhibited strong Hh inhibition.

Examination of the side chains included in this defined set reveals thatthe criteria for potent inhibition of the Hh pathway is permissive toextension of the side chain beyond 3 carbons in length, as elongation upto n-octane (compound 7m) generally resulted in increased potency for Hhpathway inhibition and MB proliferation. Retention of potency for Hhpathway inhibition with compound 7n and loss of pathway specificactivity with compound 7q suggests that there is some allowance for bulkat the distal end of these extensions, but not to the extent necessaryto accommodate a benzophenone group, similar to the herein describedobservations for HUVEC proliferation. Pathway inhibition was alsopermissive to branching on the α or γ carbon as demonstrated byItraconazole, 7h, 7i, and 7j. Compound 7k appears to be an exception,which exception, in the context of the activity demonstrated by 7j,suggests that branching from the a position was not permissive tomoieties with either large displacement volume or restricted rotationaldegrees of freedom. Pathway inhibition was also favored in compound 7r,containing a terminal alkyne. Alkene and alkyne linkages between γ and δcarbons were also active against the pathway.

Taken together, the SAR trends and defined side chain sets derived fromthese analyses provide criteria for examining the relationship betweenactivities against the Hh pathway and those targeting glycosylation andHUVEC proliferation. Overall, divergence between the activity of 7g and7m demonstrate MB selectivity for saturated alkane chains greater than 4carbons in length. Functional groups associated with the distal ends of7n, 7p, and 7u further differentiate these activities and identify apreference for small, polar cyano and azido functional groups in thepharmacophore associated with effects on HUVEC proliferation and VEGFR2glycosylation, whereas a more bulky, hydrophobic phenyl group ispreferred for activity against Hh signaling. Compounds 7k and 7lidentify large groups proximal to the core triazolone ring as havingimproved activity in HUVEC proliferation and favoring inhibition ofVEGFR2 glycosylation, whereas these structures were disfavored forinhibition of the Hh pathway. Interestingly, the sec-pentyl modificationassociated with compound 7h represents the only side chain compositionin the analogue set that simultaneously inhibits glycosylation and theHh pathway. Most notably, this compound was also the only analogdemonstrating increased potency across all parameters as compared withItraconazole.

Through N-alkylation of the triazolone moiety in three differentsynthetic routes, a focused library of twenty-five side chain analogs ofItraconazole was synthesized. These analogs were screened for effects onHUVEC proliferation, VEGFR2 glycosylation, inhibition of Gli1transcription in MB cells, and inhibition of MB proliferation. Analogsthat were robust inhibitors of glycosylation were significantlyassociated with greater potency against HUVEC proliferation, suggestingthat glycosylation inhibition contributes to the overall antiangiogenicactivity of Itraconazole. The SAR study on antiangiogenic activitysuggests that the binding site of the side chain may be mainlyhydrophobic and relatively deep and flexible. It was also possible toincorporate additional functional groups, such as terminal alkyne,azido, and cyano, which led to enhancement of antiangiogenic activity.However, to achieve potent inhibition against VEGFR2 glycosylation,there were more stringent structural and functional requirements for theside chain, mainly that side chains of at least four carbons withbranching at the α or β position were generally required for highpotency. Surprisingly, it was found that some compounds with relativelypotent inhibitory activity against MB proliferation were not similarlypotent inhibitors of Gli1 transcription. Of the derivatives tested, 12were found to exert strong Hh pathway inhibition associated with theiranti-proliferative effects in MB, as indicated by inhibition Gli1transcript levels. These compounds were generally characterized by sidechains with extensions of at least three carbons in length and lackingbranching from the β position. The distinct trends demonstrated by theSAR of these two molecular activities, together with the lack ofcorrelation between the potency of the analogs in HUVEC and MBproliferation, suggest that Itraconazole's effect on the Hh pathway islargely unrelated to the activity of Itraconazole in HUVEC. It ispossible that the effects of Itraconazole on HUVEC and Hh signalingpathway are mediated by distinct molecular targets. Together, theresults presented herein have deepened the understanding of the role ofthe Itraconazole side chain in the antiangiogenic and anti-Hh pathwayactivities of this drug and will likely facilitate the design of futureanalogs with increased potency for specific activities. Analogs withselectivity for one or more pathways may be useful in animal studies toclarify the role for each activity in in vivo tumor suppression.

The following examples are intended to illustrate but not limit theinvention.

General Experimental Conditions

Reactions were carried out in oven-dried glassware. All reagents werepurchased from commercial sources and were used without furtherpurification unless noted. Unless stated otherwise, all reactions werecarried out under a positive pressure of argon monitored by Merckprecoated silica gel 60E-254 plates and visualized using 254 nm UVlight. Column chromatography was performed on silica gel (200-400 mesh,Merck). The ratio between silica gel and crude product ranged from 100to 50:1 (w/w). NMR data were collected on a Varian Unity-400 (400 MHz¹H, 100 MHz ¹³C) machine in the Department of Pharmacology and MolecularSciences, the Johns Hopkins University. ¹H NMR spectra were obtained indeuteriochloroform (CDCI₃) with either tetramethylsilane (TMS, δ=0.00for ¹H) or chloroform (CHCl₃, δ=7.27 for ¹H) as an internal reference.¹³C NMR spectra were proton decoupled and were in CDCl₃ with either TMS(δ=0.0 for ¹³C) or CHCl₃ (δ=77.0 for ¹³C) as an internal reference.Chemical shifts are reported in ppm (δ). Data are presented in the form:chemical shift (multiplicity, coupling constants, and integration). ¹Hdata are reported as though they were first order. The errors betweenthe coupling constants for two coupled protons were less than 0.5 Hz,and the average number was reported. Low-resolution mass spectra wereobtained on a API 150EX™ single quadrupole LC/ESI-MS system in theDepartment of Pharmacology and Molecular Sciences or on a VoyagerDE-STR, MALDI-TOF instrument at the AB Mass Spectrometry/ProteomicsFacility at the Johns Hopkins University. The MALDI-samples wereprepared by mixing droplets of the sample solutions in chloroform ormethanol and 2,5-dihydroxybenzoic acid solution in acetone, where thelatter served as the matrix. The reported purity values were obtainedwith a JASCO PU-20895 Plus quaternary pump system, using an MD-2010 PlusPDA detector at the wavelength of 256 nm, and a Varian Microsorb-MV100-5 C18 column. The eluant consisted of acetonitrile and 0.125%diethylamine in water, the ratio and flow rate of which depends on thecompound. When the purity derived from HPLC analysis is greater than99%, it is reported as >99%.

The experimental procedures and analytical data for new compounds 3h,3l, 3n-3t, 3v-3x, 4a-4n, 5a-5q, 11-13 and 14a-14c; VEGFR2 glycosylationscoring, characterization of MB culture system, experimentallydetermined IC₉₀ and associated ΔΔ Ct values, and correlations betweenGli1 inhibition and MB proliferation as well as VEGFR2 glycosylation aredescribed below.

Compounds 3h, 3l, 3n-3t, 3v-3x, 4a-4n, 5a-5q, 11-13 and 14a-14c can besynthesized according to the following synthetic procedures.

Tosylation or brosylation of alcohols: To a solution of alcohol (1equiv.), Et₃N (1.5-2.0 equiv.), and N, N-dimethylamino-pyridine (DMAP,0.5-1 equiv.) in CH₂Cl₂ was slowly added a solution of p-toluenesulfonicchloride (TsCl) or 4-bromobenzene-1-sulfonyl chloride (BsCl) (1.1-1.3equiv.) in CH₂Cl₂ at 0° C. The reaction mixture was stirred at 0° C. for1 h, and then warmed to room temperature for another 3 h. After dilutedwith water, the reaction mixture was extracted with more CH₂Cl₂. Theorganic layer was combined, dried (Na₂SO₄), filtered, and concentratedto yield the crude product, which was then purified by columnchromatography.

Alkylation of triazolone (Method A): To a suspension of triazolone 2 or13 (1 equiv.) in DMSO was added K₂CO₃ (2.0-2.2 equiv.) or CS₂CO₃(1.6-2.0 equiv.). The resulting mixture was stirred at room temperaturefor 1 h. After the addition of alkyl bromide, alkyl tosylate, or alkylbrosylate (1.3-2.0 equiv.), the temperature was increased to 80° C. andkept overnight. In most cases, KI (0.2-0.5 equiv.) was also added toaccelerate the reaction. After cooling to room temperature, the reactionmixture was diluted with water and extracted with CH₂Cl₂. The combinedorganic layer was dried (Na₂SO₄), filtered, and concentrated to yieldthe crude product, which was purified by column chromatography.

Alkylation of triazolone (Method B): To a suspension of triazolone 2 (1equiv.) in DMSO was added K₂CO₃ (1.6-6.6 equiv.) or Cs₂CO₃ (1.6-2.0equiv.), 18-Crown-6 (1 equiv.), and alkyl bromide or alkyl tosylate(1.3-6.0 equiv.). The resulting mixture was stirred at room temperatureovernight, followed by the dilution with water and the extraction withCH₂Cl₂. The combined organic layer was dried (Na₂SO₄), filtered, andconcentrated to yield the crude product, which was purified by columnchromatography.

De-methylation of the phenolic methoxy group: The suspension of compound4a-4n (1 equiv.) in 48% aqueous HBr was heated to reflux for 6 h. Aftercooling to room temperature, the solution was neutralized with saturatedaqueous Na₂CO₃ and extracted with CH₂Cl₂. The combined organic layer wasdried (Na₂SO₄), filtered, and concentrated to yield the product. Unlessotherwise stated, the resulted product was used directly for the nextcoupling reaction without any purification.

Removal of the methoxymethoxy (MOM) protecting group: To a solution ofcompound 14a-14c (1 equiv.) in CH₂Cl₂ was added trifluoroacetic acid(TFA) in large excess. The resulting mixture was stirred at roomtemperature and monitored by TLC. Once the reaction was over, thesolution was neutralized with saturated aqueous Na₂CO₃ and extractedwith CH₂Cl₂. The combined organic layer was dried (Na₂SO₄), filtered,and concentrated to yield the product. Unless otherwise stated, theresulted product was used directly for the next coupling reactionwithout any purification.

Synthesis of diazirine: To a 100 mL thick wall pressure vesselcontaining a ketone compound (1 equiv.) in an ice bath was added 7Nammonia in methanol (MeOH) (7 equiv.). After the vessel was sealed, thereaction mixture was stirred at 0° C. for 4 h. Hydroxylamine O-Sulfonicacid (1.15 equiv.) was dissolved in methanol and then added drop-wiseinto the reaction mixture. After stirring overnight, most ammonia wasremoved by gently blowing air through the suspension using a glasspipette, and then the white precipitate was filtered off After solventswere removed under vacuum, the residue was re-dissolved in methanolfollowed by the addition of triethylamine (1.5 equiv.). Subsequently,the solution was cooled to 0° C., and iodine was slowly added until thecolor of iodine persists for 1 min After 2 h, methanol was evaporatedand the reaction mixture was extracted with ether and dried (Na₂SO₄),filtered, and concentrated to yield the crude product, which was useddirectly for the next reaction without any purification.

1-(4-(Methoxymethoxy)phenyl)-4-(4-nitrophenyl)piperazine (11): To amixture of 10 (263.4 mg, 0.88 mmol) and diisopropylamine (DIPEA) (170.6mg, 1.32 mmol) in CH₂Cl₂ (12 mL) was added slowly chloromethyl methylether (77.9 mg, 0.97 mmol) at room temperature. The reaction was stirredfor 16 h, and then quenched by the addition of saturated aqueousammonium chloride (10 mL). The resulting solution was extracted withmore CH₂O₂, dried (Na₂SO₄), filtered, and concentrated to yield thecrude product, which was purified by column chromatography (neatCH₂Cl₂→100:1 CH₂Cl₂-Acetone) to afford 11 (250.8 mg, 83%) as a yellowamorphous solid: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 8.20-8.08 (m, 2H),7.07-6.97 (m, 2H), 6.97-6.82 (m, 4H), 5.13 (s, 2H), 3.62-3.51 (m, 4H),3.48 (s, 3H), 3.30-3.18 (m, 4H); ¹³C NMR (100 MHz, CDCl₃, δ_(C)) 154.99,151.98, 146.31, 138.84, 126.18, 118.59, 117.58, 113.04, 95.28, 56.13,50.42, 47.43. MALDI-MS: 344.2 (M+H+), 366.2 (M+Na+).

4-(4-(4-(Methoxymethoxy)phenyl)piperazin-1-yl)aniline (12): The nitrogroup in 11 (250.8 mg, 0.73 mmol) was reduced in the presence of 10%Pd/C (46.8 mg, 5% mole ratio) and hydrazine monohydrate (365.4 mg, 7.3mmol) in EtOH (10 mL) at reflux. Once the starting material was fullyconsumed (about 3.5 h), the reaction mixture was filtered through aCelite pad and concentrated to afford 12 as white amorphous solid (226.5mg, 99%), which was used directly for the next step without anypurification: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 7.07-6.81 (m, 6H),6.72-6.63 (m, 2H), 5.13 (s, 2H), 3.49 (d, J=1.3 Hz, 3H), 3.46-3.34 (m,2H), 3.22 (qd, J=7.1, 3.1 Hz, 8H); ¹³C NMR (100 MHz, CDCl₃, δ_(C))151.53, 146.97, 144.63, 140.64, 119.05, 118.30, 117.51, 116.43, 95.36,56.10, 51.45, 50.93. MALDI-MS: 314.2 (M+H⁺), 336.2 (M+Na⁺).

4-(4-(4-(4-(Methoxymethoxy)phenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one(13): To a solution of 12 (349.1 mg, 1.11 mmol) and pyridine (131.7 mg,1.67 mmol) in CH₃CN (5 mL), phenyl chloroformate (191.9 mg, 1.23 mmol)was dropwise added at 0° C. The reaction mixture was allowed to warm toroom temperature overnight. Then water (10 mL) was added and the mixturewas stirred for 30 min. The precipitated light gray solid was filtered,washed with acetonitrile, and then dried under vacuum to obtain thecarbamate intermediate (428.3 mg, 89%). To a suspension of carbamate(268.8 mg, 0.62 mmol) in 1,4-dioxolane (5 mL) was added hydrazinemonohydrate (170.7 mg, 3.41 mmol). The resulting mixture was heated toreflux for 4 h, cooled down to room temperature, and then diluted withwater. The precipitate was filtered, washed with acetonitrile, and thendried under vacuum to obtain the hydrazinecarboxamide intermediate(142.1 mg, 62%) as a light orange solid. The mixture ofhydrazinecarboxamide (74.5 mg, 0.20 mmol) and formamidine acetate (114.5mg, 1.10 mmol) in 1-propanol (3 mL) was heated to reflux for 3 h. Aftercooling to room temperature, the reaction mixture was diluted withwater. The solid was filtered, washed with 50% aqueous 1-propanol, andthen dried under vacuum to give 13 (44.1 mg, 63%) as an off-whiteamorphous solid: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 11.86 (s, 1H), 8.23 (s,1H), 7.46 (d, J=9.0 Hz, 2H), 7.08 (d, J=9.1 Hz, 2H), 6.93 (d, J=2.2 Hz,4H), 5.07 (s, 2H), 3.34 (s, 3H), 3.31-3.24 (m, 4H), 3.18-3.13 (m, 4H).MALDI-MS: 382.2 (M+H⁺), 404.2 (M+Na⁺).

4-(4-(4-(4-Methoxyphenyl)piperazin-1-yl)phenyl)-1-methyl-1H-1,2,4-triazol-5(4H)-one(4a). This compound was synthesized as an off-white amorphous solid from2 (99.7 mg, 0.284 mmol), methyl tosylated 3a (68.6 mg, 0.369 mmol),Cs₂CO₃ (148.0 mg, 0.454 mmol), and 18-Crown-6 (75.0 mg, 0.284 mmol) in21% yield by following general procedure 1.3: ¹H NMR (400 MHz, CDCl₃,δ_(H)) 7.60 (s, 1H), 7.45-7.34 (m, 2H), 7.07-6.83 (m, 6H), 3.78 (s, 3H),3.53 (s, 3H), 3.40-3.32 (m, 4H), 3.28-3.19 (m, 4H); ¹³C NMR (100 MHz,CDCl₃, δ_(C)) 154.40, 152.61, 150.93, 145.66, 134.23, 125.90, 123.90,118.83, 116.85, 114.73, 55.80, 51.02, 49.42, 32.90. MALDI-MS: 366.2(M+H⁺), 388.2 (M+Na⁺).

4-(4-(4-(4-Hydroxyphenyl)piperazin-1-yl)phenyl)-1-methyl-1H-1,2,4-triazol-5(4H)-one(5a). This compound was synthesized as a white amorphous solid from 4a(21.8 mg, 0.060 mmol) in 48% aqueous HBr (1 mL) in 96% yield byfollowing general procedure 1.4: MALDI-MS: 352.2 (M+H⁺), 374.2 (M+Na⁺).

1-Ethyl-4-(4-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one(4b). This compound was synthesized as an off-white amorphous solid from2 (60.0 mg, 0.171 mmol), ethyl tosylated 3b (44.5 mg, 0.222 mmol), K₂CO₃(37.8 mg, 0.273 mmol), and 18-Crown-6 (45.2 mg, 0.171 mmol) in 32% yieldby following general procedure 1.3: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 7.61(s, 1H), 7.40 (d, J=8.9 Hz, 2H), 7.08-6.92 (m, 4H), 6.92-6.82 (m, 2H),3.91 (q, J=12 Hz, 2H), 3.78 (s, 3H), 3.36 (dd, J=6.2, 3.8 Hz, 4H), 3.23(dd, J=6.2, 3.8 Hz, 4H), 1.39 (t, J=7.2 Hz, 3H); ¹³C NMR (100 MHz,CDCl₃, δ_(C)) 154.40, 152.10, 150.85, 145.65, 134.25, 125.99, 123.86,118.84, 116.85, 114.73, 55.79, 51.02, 49.43, 40.78, 14.11. MALDI-MS:380.2 (M+H⁺), 402.2 (M+Na⁺).

1-Ethyl-4-(4-(4-(4-Hydroxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one(5b). This compound was synthesized as a white amorphous solid from 4b(20.9 mg, 0.055 mmol) in 48% aqueous HBr (1 mL) in 93% yield byfollowing general procedure 1.4: MALDI-MS: 366.2 (M+H⁺), 388.2 (M+Na⁺).

4-(4-(4-(4-Methoxyphenyl)piperazin-1-yl)phenyl)-1-propyl-1H-1,2,4-triazol-5(4H)-one(4c). This compound was synthesized as a yellowish amorphous solid from2 (69.5 mg, 0.198 mmol), 1-bromopropane 3c (38.9 mg, 0.316 mmol), K₂CO₃(54.7 mg, 0.396 mmol), and 18-Crown-6 (52.3 mg, 0.198 mmol) in 69% yieldby following general procedure 1.3: ¹H NMR (400 MHz, CDCl³, δ_(H)) 7.60(s, 1H), 7.51-7.36 (m, 2H), 7.07-6.92 (m, 4H), 6.92-6.80 (m, 2H),3.83-3.78 (m, 2H), 3.76 (s, 3H), 3.39-3.32 (m, 4H), 3.25-3.18 (m, 4H),1.93-1.72 (m, 2H), 0.97 (t, J=7.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃,δ_(C)) 154.48, 152.39, 150.78, 145.48, 134.17, 126.06, 123.77, 118.88,116.86, 114.73, 55.78, 51.08, 49.40, 47.40, 22.27, 11.35. MALDI-MS:394.2 (M+H⁺), 416.2 (M+Na⁺).

4-(4-(4-(4-Hydroxyphenyl)piperazin-1-yl)phenyl)-1-propyl-1H-1,2,4-triazol-5(4H)-one(5c). This compound was synthesized as a white amorphous solid from 4c(53.6 mg, 0.136 mmol) in 48% aqueous HBr (1.5 mL) in 97% yield byfollowing general procedure 1.4: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 7.62 (s,1H), 7.38 (d, J=8.6 Hz, 2H), 7.06-6.90 (m, 4H), 6.74 (d, J=8.4 Hz, 2H),3.83 (t, J=7.1 Hz, 2H), 3.37-3.31 (m, 4H), 3.24-3.18 (m, 4H), 1.83 (dd,J=14.5, 7.2 Hz, 2H), 0.98 (t, J=7.3 Hz, 3H). MALDI-MS: 380.2 (M+H⁺),402.2 (M+Na⁺).

1-Isopropyl-4-(4-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one(4d). This compound was synthesized as a yellowish amorphous solid from2 (60.0 mg, 0.171 mmol), isopropyl tosylate 3d (47.6 mg, 0.222 mmol),K₂CO₃ (37.8 mg, 0.273 mmol), and 18-Crown-6 (45.2 mg, 0.171 mmol) in 47%yield by following general procedure 1.3: ¹H NMR (400 MHz, CDCl₃, δ_(H))7.60 (s, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.11-6.83 (m, 6H), 4.56 (dt,J=13.4, 6.7 Hz, 1H), 3.78 (d, J=0.8 Hz, 3H), 3.47-3.31 (m, 4H),3.30-3.15 (m, 4H), 1.41 (d, J=6.7 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃,δ_(C)) 154.39, 151.67, 150.81, 145.69, 134.13, 126.03, 123.86, 118.82,116.84, 114.73, 55.79, 51.01, 49.46, 47.17, 21.40. MALDI-MS: 394.2(M+H⁺), 416.2 (M+Na⁺).

4-(4-(4-(4-Hydroxyphenyl)piperazin-1-yl)phenyl)-1-isopropyl-1H-1,2,4-triazol-5(4H)-one(5d). This compound was synthesized as a white amorphous solid from 4d(31.6 mg, 0.080 mmol) in 48% aqueous HBr (1.0 mL) in 96% yield byfollowing general procedure 1.4: MALDI-MS: 380.2 (M+H⁺), 402.2 (M+Na⁺).

1-Butyl-4-(4-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one(4e). This compound was synthesized as a yellowish amorphous solid from2 (132.0 mg, 0.376 mmol), 1-bromobutane 3e (82.4 mg, 0.601 mmol), K₂CO₃(103.9 mg, 0.752 mmol), and KI (31.2 mg, 0.188 mmol) in 73% yield byfollowing general procedure 1.2: ¹H NMR (400 MHz, CDCl³, δ_(H)) 7.60 (s,1H), 7.47-7.35 (m, 2H), 7.07-6.81 (m, 6H), 3.85 (t, J=7.2 Hz, 2H), 3.78(s, 3H), 3.36 (dd, J=6.3, 3.8 Hz, 4H), 3.22 (dd, J=6.3, 3.8 Hz, 4H),1.78 (dq, J=12.7, 7.6 Hz, 2H), 1.40 (dq, J=14.7, 7.4 Hz, 2H), 0.96 (t,J=7.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃, δ_(C)) 154.40, 152.35, 150.84,145.69, 134.13, 126.05, 123.78, 118.83, 116.85, 114.73, 55.79, 51.01,49.46, 45.55, 30.92, 20.02, 13.89. MALDI-MS: 408.2 (M+H⁺), 430.2(M+Na⁺).

1-Butyl-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one(5e). This compound was synthesized as a white amorphous solid from 4e(144.6 mg, 0.355 mmol) in 48% aqueous HBr (3.0 mL) in 99% yield byfollowing general procedure 1.4: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 7.61 (s,1H), 7.40 (d, J=9.0 Hz, 2H), 7.02 (d, J=9.0 Hz, 2H), 6.90 (d, J=8.9 Hz,2H), 6.79 (d, J=8.9 Hz, 2H), 4.58 (s, 1H), 3.85 (t, J=7.2 Hz, 2H), 3.36(dd, J=6.2, 3.9 Hz, 4H), 3.22 (dd, J=6.2, 3.9 Hz, 4H), 1.78 (dt, J=12.7,7.5 Hz, 2H), 1.40 (td, J=14.9, 7.5 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H).MALDI-MS: 394.2 (M+H⁺), 416.2 (M+Na⁺).

1-Isobutyl-4-(4-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one(4f). This compound was synthesized as a yellowish amorphous solid from2 (60.0 mg, 0.171 mmol), 1-bromo-2-methylpropane 3f (30.4 mg, 0.222mmol), K₂CO₃ (42.5 mg, 0.308 mmol), and KI (8.5 mg, 0.051 mmol) in 67%yield by following general procedure 1.2: ¹H NMR (400 MHz, CDCl₃, δ_(H))7.62 (s, 1H), 7.47-7.36 (m, 2H), 7.09-6.76 (m, 6H), 3.78 (s, 3H), 3.66(d, J=12 Hz, 2H), 3.35 (dd, J=6.2, 3.8 Hz, 4H), 3.22 (dd, J=6.2, 3.8 Hz,4H), 2.20 (dt, J=13.6, 6.8 Hz, 1H), 0.98 (d, J=6.8 Hz, 6H); ¹³C NMR (100MHz, CDCl³, δ_(C)) 154.38, 152.63, 150.81, 145.68, 134.07, 126.08,123.70, 118.82, 116.85, 114.72, 55.79, 53.03, 51.00, 49.46, 28.47,20.14. MALDI-MS: 408.2 (M+H⁺), 430.2 (M+Na⁺).

4-(4-(4-(4-Hydroxyphenyl)piperazin-1-yl)phenyl)-1-isobutyl-1H-1,2,4-triazol-5(4H)-one(5f). This compound was synthesized as a white amorphous solid from 4f(64.0 mg, 0.152 mmol) in 48% aqueous HBr (1.5 mL) in 91% yield byfollowing general procedure 1.4: MALDI-MS: 394.2 (M+H⁺), 416.2 (M+Na⁺).

4-(4-(4-(4-Methoxyphenyl)piperazin-1-yl)phenyl)-1-pentyl-1H-1,2,4-triazol-5(4H)-one(4g). This compound was synthesized as a yellowish amorphous solid from2 (64.4 mg, 0.183 mmol), 1-bromopentane 3g (44.3 mg, 0.293 mmol), K₂CO₃(50.6 mg, 0.366 mmol), and KI (9.1 mg, 0.055 mmol) in 53% yield byfollowing general procedure 1.2: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 7.61 (s,1H), 7.41 (d, J=8.9 Hz, 2H), 7.08-6.92 (m, 4H), 6.92-6.81 (m, 2H), 3.83(t, J=7.2 Hz, 2H), 3.77 (s, 3H), 3.42-3.31 (m, 4H), 3.22 (dd, J=6.0, 3.8Hz, 4H), 1.90-1.72 (m, 2H), 1.41-1.32 (m, 4H), 0.90 (t, J=6.9 Hz, 3H);¹³C NMR (100 MHz, CDCl₃, δ_(C)) 154.40, 152.32, 150.81, 145.63, 134.14,126.05, 123.76, 118.84, 116.85, 114.72, 55.78, 51.02, 49.44, 45.83,28.93, 28.59, 22.51, 14.22. MALDI-MS: 422.2 (M+H⁺), 444.2 (M+Na⁺).

4-(4-(4-(4-Hydroxyphenyl)piperazin-1-yl)phenyl)-1-pentyl-1H-1,2,4-triazol-5(4H)-one(5g). This compound was synthesized as a white amorphous solid from 4g(43.4 mg, 0.103 mmol) in 48% aqueous HBr (1.0 mL) in 89% yield byfollowing general procedure 1.4: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 7.62 (s,1H), 7.40 (t, J=10.1 Hz, 2H), 7.05-6.94 (m, 4H), 6.75 (d, J=8.5 Hz, 2H),3.85 (t, J=7.2 Hz, 2H), 3.48-3.40 (m, 4H), 3.43-3.35 (m, 4H), 1.90-1.72(m, 2H), 1.40-1.33 (m, 4H), 0.91 (t, J=6.9 Hz, 3H). MALDI-MS: 408.2(M+H+), 430.2 (M+Na+).

2-Pentyl tosylate (3h). This compound was synthesized as a colorless oilfrom 2-pentanol (122.0 mg, 1.384 mmol), TsCl (316.6 mg, 1.66 mmol), Et₃N(280.3 mg, 2.77 mmol), and DMAP (169.0 mg, 1.384 mmol) in 92% yield byfollowing general procedure 1.1: ¹H NMR (400 MHz, CDCl₃; δ_(H)) 7.75 (d,J=8.3 Hz, 2H), 7.30 (d, J=8.3 Hz, 2H), 4.63-4.51 (m, 1H), 2.40 (s, 3H),1.56 (dddd, J=14.0, 10.0, 7.2, 5.4 Hz, 1H), 1.49-1.35 (m, 1H), 1.35-1.04(m, 5H), 0.77 (t, J=1 A Hz, 3H); ¹³C NMR (100 MHz, CDCl₃, δ_(C)) 144.57,134.63, 129.84, 127.78, 80.55, 38.70, 21.73, 20.90, 18.28, 13.74.ESI-MS: 243.1 (M+H⁺), 265.1 (M+Na⁺).

4-(4-(4-(4-Methoxyphenyl)piperazin-1-yl)phenyl)-1-(pentan-2-yl)-1H-1,2,4-triazol-5(4H)-one(4h). This compound was synthesized as a yellowish amorphous solid from2 (70.0 mg, 0.199 mmol), 3h (79.5 mg, 0.328 mmol), K₂CO₃ (55.0 mg, 0.398mmol), and 18-Crown-6 (52.6 mg, 0.199 mmol) in 57% yield by followinggeneral procedure 1.3: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 7.61 (s, 1H), 7.41(d, J=8.6 Hz, 2H), 7.06-6.91 (m, 4H), 6.86 (d, J=8.8 Hz, 2H), 4.44-4.33(m, 1H), 3.77 (s, 3H), 3.46-3.30 (m, 4H), 3.31-3.15 (m, 4H), 1.93-1.77(m, 1H), 1.72-1.53 (m, 1H), 1.46-1.18 (m, 5H), 0.92 (t, J=7.3 Hz, 3H);¹³C NMR (100 MHz, CDCl₃, δ_(C)) 154.52, 152.13, 150.72, 145.43, 134.16,126.15, 123.73, 118.91, 116.88, 114.74, 55.78, 51.10, 51.06, 49.43,37.69, 19.88, 19.71, 14.01. MALDI-MS: 422.2 (M+H⁺), 444.2 (M+Na⁺).

4-(4-(4-(4-Hydroxyphenyl)piperazin-1-yl)phenyl)-1-pentyl-1H-1,2,4-triazol-5(4H)-one(5h). This compound was synthesized as a white amorphous solid from 4h(41.1 mg, 0.098 mmol) in 48% aqueous HBr (1.0 mL) in 97% yield byfollowing general procedure 1.4: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 7.62 (s,1H), 7.36 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.5 Hz, 2H), 6.83 (d, J=8.4 Hz,2H), 6.68 (d, J=8.5 Hz, 2H), 4.52-4.28 (m, 1H), 3.39-3.28 (m, 4H),3.25-3.14 (m, 4H), 1.94-1.78 (m, 1H), 1.64 (ddd, J=19.7, 12.6, 5.8 Hz,1H), 1.44-1.23 (m, 5H), 0.92 (t, J=7.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃,δ_(C)) 152.47, 151.60, 150.98, 144.38, 134.64, 125.52, 124.54, 119.17,116.75, 116.28, 51.48, 51.42, 49.20, 37.67, 19.87, 19.70, 14.00.MALDI-MS: 408.2 (M+H⁺), 430.2 (M+Na⁺).

1-Isopentyl-4-(4-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one(4i). This compound was synthesized as a yellowish amorphous solid from2 (64.6 mg, 0.184 mmol), 1-bromo-3-methylbutane 3i (47.2 mg, 0.313mmol), K₂CO₃ (50.8 mg, 0.368 mmol), and KI (15.3 mg, 0.092 mmol) in 56%yield by following general procedure 1.2: ¹H NMR (400 MHz, CDCl₃, δ_(H))7.61 (s, 1H), 7.40 (d, J=8.9 Hz, 2H), 6.99 (dd, J=20.1, 8.9 Hz, 4H),6.86 (d, J=9.0 Hz, 2H), 3.87 (d, J=7.1 Hz, 2H), 3.77 (s, 3H), 3.43-3.31(m, 4H), 3.28-3.14 (d, J=4.6 Hz, 4H), 1.70-1.62 (m, 3H), 0.96 (d, J=6.2Hz, 6H); ¹³C NMR (100 MHz, CDCl₃, δ_(C)) 154.47, 152.26, 150.78, 145.53,134.14, 126.07, 123.75, 118.89, 116.87, 114.72, 55.78, 51.08, 49.41,44.18, 37.57, 25.81, 22.62. MALDI-MS: 422.2 (M+H⁺), 444.2 (M+Na⁺).

4-(4-(4-(4-Hydroxyphenyl)piperazin-1-yl)phenyl)-1-isopentyl-1H-1,2,4-triazol-5(4H)-one(5i). This compound was synthesized as a white amorphous solid from 4i(43.4 mg, 0.103 mmol) in 48% aqueous HBr (1.0 mL) in 95% yield byfollowing general procedure 1.4: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 7.61 (s,1H), 7.37 (d, J=8.7 Hz, 2H), 7.02-6.91 (m, 4H), 6.73 (d, J=8.4 Hz, 2H),3.91-3.83 (m, 2H), 3.44-3.35 (m, 4H), 3.29-3.20 (m, 4H), 1.76-1.63 (m,3H), 0.96 (d, J=5.6 Hz, 6H). MALDI-MS: 408.2 (M+H⁺), 430.2 (M+Na⁺).

4-(4-(4-(4-Methoxyphenyl)piperazin-1-yl)phenyl)-1-(pentan-3-yl)-1H-1,2,4-triazol-5(4H)-one(4j). This compound was synthesized as a yellowish amorphous solid from2 (62.0 mg, 0.176 mmol), 3-bromopentane 3j (45.3 mg, 0.300 mmol), K₂CO₃(48.8 mg, 0.353 mmol), and KI (14.6 mg, 0.088 mmol) in 56% yield byfollowing general procedure 1.2: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 7.64 (s,1H), 7.53-7.39 (m, 2H), 7.07-6.93 (m, 4H), 6.93-6.81 (m, 2H), 4.14-3.97(m, 1H), 3.77 (s, 3H), 3.45-3.30 (m, 4H), 3.30-3.13 (m, 4H), 1.94-1.62(m, 4H), 0.88 (t, J=7.4 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃, δ_(C)) 154.55,153.02, 150.69, 145.42, 134.20, 126.24, 123.64, 118.94, 116.91, 114.74,58.99, 55.79, 51.14, 49.44, 27.00, 10.98. MALDI-MS: 422.2 (M+H⁺), 444.2(M+Na⁺).

4-(4-(4-(4-Hydroxyphenyl)piperazin-1-yl)phenyl)-1-(pentan-3-yl)-1H-1,2,4-triazol-5(4H)-one(5j). This compound was synthesized as a white amorphous solid from 4j(41.5 mg, 0.099 mmol) in 48% aqueous HBr (1.0 mL) in 98% yield byfollowing general procedure 1.4: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 7.64 (s,1H), 7.40 (d, J=8.9 Hz, 2H), 7.04-6.92 (m, 4H), 6.72 (d, J=8.5 Hz, 2H),4.15-3.97 (m, 1H), 3.42-3.31 (m, 4H), 3.29-3.18 (m, 4H), 1.95-1.62 (m,4H), 0.89 (t, J=7.4 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃, δ_(C)) 153.31,151.93, 150.78, 143.66, 134.54, 125.92, 124.36, 119.46, 116.94, 116.36,59.27, 51.82, 49.09, 26.99, 10.97. MALDI-MS: 408.2 (M+H⁺), 430.2(M+Na⁺).

1-Cyclohexyl-4-(4-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one(4k). This compound was synthesized as a yellowish amorphous solid from2 (70.3 mg, 0.20 mmol), cyclohexyl bromide 3k (195.7 mg, 1.20 mmol),K₂CO₃ (182.4 mg, 1.32 mmol), and 18-Crown-6 (52.9 mg, 0.20 mmol) in 24%yield by following general procedure 1.3: ¹H NMR (400 MHz, CDCl₃, δ_(H))7.59 (s, 1H), 7.50-7.36 (m, 2H), 7.09-7.01 (m, 2H), 7.01-6.92 (m, 2H),6.92-6.80 (m, 2H), 4.15 (tt, J=11.8, 3.9 Hz, 1H), 3.78 (s, 3H), 3.37(dd, J=6.2, 3.7 Hz, 4H), 3.23 (dd, J=6.2, 3.7 Hz, 4H), 2.03-1.65 (m,7H), 1.51-1.34 (m, 2H), 1.34-1.16 (m, 1H); ¹³C NMR (100 MHz, CDCl₃,δ_(C)) 154.38, 151.75, 150.81, 145.68, 134.03, 126.06, 123.89, 118.83,116.86, 114.72, 55.80, 54.34, 51.03, 49.47, 31.70, 25.66, 25.46.MALDI-MS: 434.2 (M+H⁺), 456.2 (M+Na⁺).

1-Cyclohexyl-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one(5k). This compound was synthesized as a white amorphous solid from 4k(24.2 mg, 0.056 mmol) in 48% aqueous HBr (1.0 mL) in 92% yield byfollowing general procedure 1.4: MALDI-MS: 420.2 (M+H⁺), 442.2 (M+Na⁺).

Cyclopentylmethyl tosylate (3l). This compound was synthesized as acolorless oil from cyclopentylmethanol (235.0 mg, 2.35 mmol), TsCl(581.5 mg, 3.05 mmol), Et₃N (473.2 mg, 4.70 mmol), and DMAP (287.1 mg,2.35 mmol) in 95% yield by following general procedure 1.1: ¹H NMR (400MHz, CDCl₃, δ_(H)) 7.77 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 3.88(d, J=7.1 Hz, 2H), 2.44 (s, 3H), 2.18 (dt, J=15.0, 7.5 Hz, 1H),1.80-1.62 (m, 2H), 1.62-1.41 (m, 4H), 1.25-1.09 (m, 2H); ¹³C NMR (100MHz, CDCl₃, δ_(C)) 144.83, 133.40, 130.02, 128.07, 74.51, 38.79, 29.19,25.45, 21.86. ESI-MS: 255.1 (M+H⁺), 277.1 (M+Na⁺).

1-(Cyclopentylmethyl)-4-(4-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one(4l). This compound was synthesized as a yellowish amorphous solid from2 (50.0 mg, 0.142 mmol), 3l (54.2 mg, 0.213 mmol), K₂CO₃ (39.3 mg, 0.285mmol), and KI (11.8 mg, 0.071 mmol) in 59% yield by following generalprocedure 1.2: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 7.61 (s, 1H), 7.50-7.36(m, 2H), 7.08-6.91 (m, 4H), 6.89-6.81 (m, 2H), 3.80-3.73 (m, 5H), 3.35(dd, J=6.3, 3.8 Hz, 4H), 3.22 (dd, J=6.3, 3.8 Hz, 4H), 2.49-2.39 (m,1H), 1.83-1.49 (m, 6H), 1.42-1.28 (m, 2H); ¹³C NMR (100 MHz, CDCl₃,δ_(C)) 154.38, 152.51, 150.80, 145.67, 134.01, 126.09, 123.71, 118.83,116.85, 114.72, 55.79, 51.01, 50.52, 49.47, 39.54, 30.36, 25.31.MALDI-MS: 434.2 (M+H⁺), 456.2 (M+Na⁺).

1-(Cyclopentylmethyl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one(5l). This compound was synthesized as a white amorphous solid from 4l(36.2 mg, 0.084 mmol) in 48% aqueous HBr (1.0 mL) in 94% yield byfollowing general procedure 1.4: MALDI-MS: 420.2 (M+H⁺), 442.2 (M+Na⁺).

4-(4-(4-(4-Methoxyphenyl)piperazin-1-yl)phenyl)-1-octyl-1H-1,2,4-triazol-5(4H)-one(4m). This compound was synthesized as a yellowish amorphous solid from2 (55.0 mg, 0.157 mmol), 1-bromooctane 3m (39.3 mg, 0.203 mmol), K₂CO₃(43.4 mg, 0.314 mmol), and KI (13.0 mg, 0.078 mmol) in 69% yield byfollowing general procedure 1.2: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 7.61 (s,1H), 7.47-7.35 (m, 2H), 7.07-6.99 (m, 2H), 6.99-6.94 (m, 2H), 6.94-6.85(m, 2H), 3.89-3.80 (m, 2H), 3.78 (s, 3H), 3.35 (dd, J=6.2, 3.8 Hz, 4H),3.22 (dd, J=6.2, 3.8 Hz, 4H), 1.88-1.71 (m, 2H), 1.49-1.14 (m, 10H),0.88 (t, J=6.9 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃, δ_(C)) 154.38, 152.32,150.82, 145.68, 134.13, 126.05, 123.76, 118.82, 116.84, 114.72, 55.78,51.01, 49.45, 45.87, 32.01, 29.39, 28.89, 26.80, 22.87, 14.35. MALDI-MS:464.3 (M+H⁺), 486.3 (M+Na⁺).

4-(4-(4-(4-Hydroxyphenyl)piperazin-1-yl)phenyl)-1-octyl-1H-1,2,4-triazol-5(4H)-one(5m). This compound was synthesized as a white amorphous solid from 4m(50.2 mg, 0.108 mmol) in 48% aqueous HBr (1.0 mL) in 95% yield byfollowing general procedure 1.4: MALDI-MS: 450.3 (M+H⁺), 472.3 (M+Na⁺).

6-Phenylhexyl tosylate (3n). This compound was synthesized as acolorless oil from 6-phenylhexan-1-ol (137.0 mg, 0.77 mmol), TsCl (190.7mg, 1.00 mmol), Et₃N (155.0 mg, 1.54 mmol), and DMAP (93.8 mg, 0.77mmol) in 81% yield by following general procedure 1.1: ¹H NMR (400 MHz,CDCl₃, δ_(H)) 7.87-7.77 (m, 2H), 7.35 (d, J=8.0 Hz, 2H), 7.33-7.24 (m,2H), 7.23-7.13 (m, 3H), 4.03 (t, J=6.5 Hz, 2H), 2.65-2.53 (m, 2H), 2.45(s, 3H), 1.75-1.50 (m, 4H), 1.45-1.19 (m, 4H); ¹³C NMR (100 MHz, CDCl₃,δ_(C)) 144.93, 142.73, 133.40, 130.08, 128.60, 128.52, 128.11, 125.92,70.89, 35.99, 31.44, 28.98, 28.78, 25.47, 21.88. ESI-MS: 333.1 (M+H⁺),355.1 (M+Na⁺).

4-(4-(4-(4-Methoxyphenyl)piperazin-1-yl)phenyl)-1-(6-phenylhexyl)-1H-1,2,4-triazol-5(4H)-one(4n). This compound was synthesized as a yellowish amorphous solid from2 (56.5 mg, 0.161 mmol), 3n (64.1 mg, 0.193 mmol), K₂CO₃ (44.5 mg, 0.322mmol), and KI (8.0 mg, 0.048 mmol) in 61% yield by following generalprocedure 1.2: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 7.60 (s, 1H), 7.41 (d,J=8.8 Hz, 2H), 7.32-7.23 (m, 1H), 7.22-7.13 (m, 2H), 7.03 (d, J=8.9 Hz,2H), 7.00-6.93 (m, 2H), 6.93-6.83 (m, 2H), 3.84 (t, J=7.2 Hz, 2H), 3.79(s, 3H), 3.37 (dd, J=6.2, 3.8 Hz, 4H), 3.23 (dd, J=6.1, 3.8 Hz, 4H),2.69-2.52 (m, 2H), 1.89-1.71 (m, 2H), 1.71-1.57 (m, 2H), 1.50-1.33 (m,4H); ¹³C NMR (100 MHz, CDCl₃, δ_(C)) 154.41, 152.34, 150.85, 145.67,142.89, 134.16, 128.62, 128.46, 126.02, 125.83, 123.80, 118.85, 116.86,114.74, 55.80, 51.03, 49.46, 45.82, 36.07, 31.52, 29.07, 28.82, 26.66.MALDI-MS: 512.3 (M+H⁺), 534.3 (M+Na⁺).

4-(4-(4-(4-Hydroxyphenyl)piperazin-1-yl)phenyl)-1-(6-phenylhexyl)-1H-1,2,4-triazol-5(4H)-one(5n). This compound was synthesized as a white amorphous solid from 4n(27.4 mg, 0.054 mmol) in 48% aqueous HBr (1.0 mL) in 73% yield byfollowing general procedure 1.4: MALDI-MS: 498.3 (M+H⁺), 520.3 (M+Na⁺).

Hex-3-ynyl 4-methylbenzenesulfonate (3o). This compound was synthesizedas a colorless oil from hex-3-yn-1-ol (117.0 mg, 1.19 mmol), TsCl (295.5mg, 1.55 mmol), Et₃N (181.3 mg, 1.79 mmol), and DMAP (145.6 mg, 1.19mmol) in 98% yield by following general procedure 1.1: ESI-MS: 253.1(M+H⁺), 275.1 (M+Na⁺).

1-(Hex-3-ynyl)-4-(4-(4-(4-(methoxymethoxy)phenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one(14a). This compound was synthesized as a yellowish amorphous solid from13 (56.0 mg, 0.147 mmol), 3o (48.2 mg, 0.191 mmol), K₂CO₃ (40.6 mg,0.294 mmol), and 18-Crown-6 (38.9 mg, 0.147 mmol) in 60% yield byfollowing general procedure 1.3: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 7.61 (s,1H), 7.45-7.34 (m, 2H), 7.10-6.87 (m, 6H), 5.12 (s, 2H), 3.97 (t, J=7.3Hz, 2H), 3.47 (s, 3H), 3.35 (dd, J=6.3, 3.6 Hz, 4H), 3.23 (dd, J=6.3,3.6 Hz, 4H), 2.63 (tt, J=7.3, 2.3 Hz, 2H), 2.14 (qt, J=7.5, 2.3 Hz, 2H),1.09 (t, J=7.5 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃, δ_(C)) 152.25, 151.76,150.85, 146.67, 134.50, 125.93, 123.81, 118.52, 117.50, 116.85, 95.28,83.95, 75.42, 56.10, 50.72, 49.39, 45.03, 19.25, 14.34, 12.62. MALDI-MS:462.2 (M+H⁺), 484.2 (M+Na⁺).

1-(Hex-3-yayl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one(5o). This compound was synthesized as a white amorphous solid from 4o(40.8 mg, 0.088 mmol) in 99% yield by following general procedure 1.5:¹H NMR (400 MHz, CDCl₃, δ_(H)) 7.61 (s, 1H), 7.44-7.30 (m, 2H),7.07-6.92 (m, 2H), 6.86 (d, J=8.9 Hz, 2H), 6.72 (d, J=8.9 Hz, 2H), 5.52(br s, 1H), 3.99 (t, J=7.2 Hz, 2H), 3.42-3.28 (m, 4H), 3.28-3.13 (m,4H), 2.65 (tt, J=7.2, 2.3 Hz, 2H), 2.15 (qt, J=7.5, 2.3 Hz, 2H), 1.10(t, J=7.5 Hz, 3H). MALDI-MS: 418.2 (M+H⁺), 440.2 (M+Na⁺).

6-Azidohexyl 4-bromobenzenesulfonate (3p). To a flask containing6-bromo-hexanol s1 (500.0 mg, 2.76 mmol) was added DMF (5.0 mL) followedby sodium azide (500.0 mg, 8.3 mmol). The reaction mixture was heated to110° C. for 12 h. After cooling to room temperature, the reactionmixture was diluted with water and extracted with ether. The organiclayer was combined, dried over Na₂SO₄, concentrated to yield the crudeproduct, which was purified by column chromatography (10:1→3:1Hexanes-Ethyl Acetate) to afford s2 (375.6 mg, 95%) as a light yellowoil: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 3.62 (t, J=6.6 Hz, 2H), 3.25 (t,J=6.9 Hz, 2H), 1.75 (s, 1H), 1.67-1.48 (m, 4H), 1.46-1.30 (m, 4H).

Compound 3p was synthesized as a colorless oil from s2 (463.8 mg, 3.24mmol), BsCl (1.08 g, 4.21 mmol), Et₃N (655.7 mg, 6.48 mmol), and DMAP(197.9 mg, 1.62 mmol) in 79% yield by following general procedure 1.1:¹H NMR (400 MHz, CDCl₃, δ_(H)) 7.77 (d, J=8.3 Hz, 2H), 7.70 (d, J=8.3Hz, 2H), 4.06 (t, J=6.4 Hz, 2H), 3.24 (t, J=6.8 Hz, 2H), 1.73-1.62 (m,2H), 1.61-1.50 (m, 2H), 1.41-1.29 (m, 4H). ESI-MS: 362.0 (M+H⁺), 384.0(M+Na⁺).

1-(6-Azidohexyl)-4-(4-(4-(4-(methoxymethoxy)phenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one(14b). This compound was synthesized as a yellowish amorphous solid from13 (114.4 mg, 0.30 mmol), 3p (130.4 mg, 0.36 mmol), and Cs₂CO₃ (146.6mg, 0.45 mmol) in 62% yield by following general procedure 1.2: ¹H NMR(400 MHz, CDCl₃, δ_(H)) 7.61 (s, 1H), 7.41 (d, J=9.0 Hz, 2H), 7.08-6.93(m, 6H), 5.13 (s, 2H), 3.85 (t, J=7.1 Hz, 2H), 3.48 (s, 3H), 3.41-3.33(m, 4H), 3.31-3.22 (m, 6H), 1.88-1.74 (m, 2H), 1.61 (dt, J=14.0, 7.0 Hz,2H), 1.52-1.35 (m, 4H). ESI-MS: 507.3 (M+H⁺), 529.3 (M+Na⁺).

1-(6-Azidohexyl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one(5p). This compound was synthesized as a white amorphous solid from 4p(268.1 mg, 0.53 mmol) in 51% yield by following general procedure 1.5:¹H NMR (400 MHz, CDCl₃, δ_(H)) 7.61 (s, 1H), 7.37 (d, J=9.0 Hz, 2H),6.98 (d, J=9.0 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 6.71 (d, J=8.8 Hz, 2H),3.86 (t, J=7.1 Hz, 2H), 3.42-3.30 (m, 4H), 3.28-3.19 (m, 6H), 1.90-1.72(m, 2H), 1.65-1.56 (m, 2H), 1.49-1.34 (m, 4H). MALDI-MS: 463.2 (M+H⁺),485.2 (M+Na⁺).

4-(6-Hydroxyhexyloxy)benzophenone (3q). A solution of4-hydroxybenzophenone s3 (200 mg, 1.01 mmol) and 2.0 g of K₂CO₃ (101.0mg, 0.731 mmol) in DMF (3 mL) was stirred at 100° C. for 30 min. Asolution of 6-bromo-hexanol s1 (200.0 mg, 1.10 mmol) in 2 mL of DMF wasthen added dropwise. After addition, the reaction mixture was stirred at100° C. for 4 h. Then it was cooled, poured into water, and extractedwith CH₂Cl₂. The extract was dried over Na₂SO₄, concentrated to yieldthe crude product, which was purified by column chromatography (10:1→2:1Hexanes-Ethyl Acetate) to afford s4 (298.7 mg, 91%) as a white amorphoussolid: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 7.75-7.69 (m, 2H), 7.68-7.63 (m,2H), 7.46 (t, J=8.3 Hz, 1H), 7.37 (t, J—7.5 Hz, 2H), 6.86 (d, J=5.8 Hz,2H), 3.93 (t, J=6.5 Hz, 2H), 3.64-3.47 (m, 2H), 3.04 (s, 1H), 1.82-1.64(m, 2H), 1.62-1.22 (m, 6H); ¹³C NMR (100 MHz, CDCl₃, δ_(H)) 195.84,163.06, 161.45, 138.38, 132.75, 132.10, 129.86, 128.36, 114.21, 68.32,62.60, 32.76, 29.24, 26.01, 25.75. ESI-MS: 299.2 (M+H⁺), 321.2 (M+Na⁺).

Compound 3q was synthesized as a colorless oil from s4 (335.6 mg, 1.12mmol), TsCl (278.3, 1.46 mmol), Et₃N (225.7 mg, 2.24 mmol), and DMAP(136.8 mg, 1.12 mmol) in 83% yield by following general procedure 1.1:¹H NMR (400 MHz, CDCl₃, δ_(H)) 7.82-7.64 (m, 6H), 7.57-7.46 (m, 1H),7.44-7.38 (m, 2H), 7.29 (d, J=8.5 Hz, 2H), 6.96-6.83 (m, 2H), 4.02-3.93(m, 4H), 2.37 (s, 3H), 1.79-1.48 (m, 4H), 1.48-1.25 (m, 4H); ¹³C NMR(100 MHz, CDCl₃, δ_(H)) 195.58, 162.95, 161.28, 144.98, 138.47, 133.29,132.72, 132.09, 130.08, 129.86, 128.40, 128.02, 114.22, 70.74, 68.15,29.05, 28.92, 25.59, 25.34, 21.81. ESI-MS: 453.2 (M+H⁺), 475.2 (M+Na⁺).

1-(6-(4-Benzoylphenoxy)hexyl)-4-(4-(4-(4-(methoxymethoxy)phenyl)piperazin-1-yl)phenyl)-1H,2,4-triazol-5(4H)-one(14c). This compound was synthesized as a yellowish amorphous solid from13 (57.2 mg, 0.150 mmol), 3q (82.6 mg, 0.183 mmol), and K₂CO₃ (41.5 mg,0.300 mmol) in 36% yield by following general procedure 1.2: ¹H NMR (400MHz, CDCl₃, δ_(H)) 7.92-7.70 (m, 4H), 7.61 (s, 1H), 7.59-7.52 (m, 1H),7.50-7.37 (m, 4H), 7.12-6.83 (m, 8H), 5.12 (s, 2H), 4.03 (t, J=6.4 Hz,2H), 3.87 (t, J=7.1 Hz, 2H), 3.48 (s, 3H), 3.35 (dd, J=6.3, 3.7 Hz, 4H),3.23 (dd, J=6.3, 3.7 Hz, 4H), 1.99-1.75 (m, 4H), 1.65-1.37 (m, 4H); ¹³CNMR (100 MHz, CDCl₃, δ_(H)) 195.76, 163.01, 152.37, 151.76, 150.84,146.69, 138.56, 134.24, 132.78, 132.05, 130.13, 129.94, 128.39, 125.97,123.75, 118.51, 117.51, 116.84, 114.24, 95.29, 68.26, 56.10, 50.70,49.38, 45.66, 29.15, 28.77, 26.47, 25.82. ESI-MS: 662.3 (M+H⁺), 684.3(M+Na⁺).

1-(6-(4-Benzoylphenoxy)hexyl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one(5q). This compound was synthesized as a white amorphous solid from 4q(38.1 mg, 0.05 mmol) in 99% yield by following general procedure 1.5: ¹HNMR (400 MHz, CDCl₃, δ_(H)) 7.89-7.71 (m, 4H), 7.62 (s, 1H), 7.56 (ddd,J=6.7, 3.9, 1.3 Hz, 1H), 7.50-7.42 (m, 2H), 7.35 (d, J=8.9 Hz, 2H),7.05-6.88 (m, 4H), 6.82 (t, J=6.1 Hz, 2H), 6.71 (d, J=8.9 Hz, 2H), 4.03(d, J=7.1 Hz, 2H), 3.89 (t, J=7.1 Hz, 2H), 3.40-3.26 (m, 4H), 3.26-3.09(m, 4H), 1.95-1.73 (m, 4H), 1.60-1.37 (m, 4H); ¹³C NMR (100 MHz, CDCl₃,δ_(H)) 195.98, 163.07, 152.67, 151.30, 151.06, 144.86, 138.50, 134.63,132.84, 132.13, 130.07, 129.98, 128.42, 125.43, 124.41, 119.07, 116.70,116.23, 114.28, 68.28, 51.30, 49.24, 45.83, 29.15, 28.77, 26.46, 25.79.ESI-MS: 618.3 (M+H⁺), 640.3 (M+Na⁺).

Pent-4-ynyl 4-methylbenzenesulfonate (3r). This compound was synthesizedas a colorless oil from pent-4-yn-1-ol (145.0 mg, 1.72 mmol), TsCl(426.3 mg, 2.24 mmol), Et₃N (349.4 mg, 3.44 mmol), and DMAP (210.1 mg,1.72 mmol) in 74% yield by following general procedure 1.1: ¹H NMR (400MHz, CDCl₃, δ_(H)) 7.77 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H),4.24-3.97 (m, 2H), 2.42 (s, 3H), 2.23 (td, J=6.9, 2.6 Hz, 2H), 1.99-1.67(m, 3H); ¹³C NMR (100 MHz, CDCl₃, δ_(H)) 145.06, 133.09, 130.09, 128.12,82.33, 69.68, 68.98, 27.91, 21.85, 14.90. ESI-MS: 239.1 (M+H⁺), 261.1(M+Na⁺).

(E)-Hex-3-enyl 4-methylbenzenesulfonate (3s). This compound wassynthesized as a colorless oil from (E)-hex-3-en-1-ol (130.0 mg, 1.30mmol), TsCl (322.2 mg, 1.69 mmol), Et₃N (196.6 mg, 1.95 mmol), and DMAP(158.8 mg, 1.30 mmol) in 99% yield by following general procedure 1.1:¹H NMR (400 MHz, CDCl₃, δ_(H)) 7.74 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0Hz, 2H), 5.50 (dtt, J=15.3, 6.3, 1.3 Hz, 1H), 5.27-5.14 (m, 1H), 4.00(t, J 6.9 Hz, 2H), 2.43 (s, 3H), 2.36-2.23 (m, 2H), 2.03-1.86 (m, 2H),0.91 (t, J=7.5 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃, δ_(H)) 144.90, 136.27,133.43, 130.01, 128.10, 122.71, 70.39, 32.28, 25.74, 21.84, 13.72.ESI-MS: 255.1 (M+H⁺), 277.1 (M+Na⁺).

(Z)-Hex-3-enyl 4-methylbenzenesulfonate (3t). This compound wassynthesized as a colorless oil from (E)-hex-3-en-1-ol (70.0 mg, 0.70mmol), TsCl (173.5 mg, 0.91 mmol), Et₃N (109.2 mg, 1.05 mmol), and DMAP(85.5 mg, 0.70 mmol) in 99% yield by following general procedure 1.1: ¹HNMR (400 MHz, CDCl₃, δ_(H)) 7.78 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.1 Hz,2H), 5.58-5.35 (m, 1H), 5.28-5.08 (m, 1H), 3.99 (t, J=7.0 Hz, 2H), 2.44(s, 3H), 2.42-2.31 (m, 2H), 2.07-1.90 (m, 2H), 0.91 (t, J=7.5 Hz, 3H);¹³C NMR (100 MHz, CDCl₃, δ_(H)) 144.94, 135.73, 133.33, 130.03, 128.11,122.27, 70.06, 27.18, 21.86, 20.82, 14.30. ESI-MS: 255.1 (M+H⁺), 277.1(M+Na⁺).

(3-Ethyloxetan-3-yl)methyl 4-methylbenzenesulfonate (3v). This compoundwas synthesized as a colorless oil from (3-ethyloxetan-3-yl)methanol(122.4 mg, 1.05 mmol), TsCl (261.2 mg, 1.37 mmol), Et₃N (159.4 mg, 1.58mmol), and DMAP (128.8 mg, 1.05 mmol) in 91% yield by following generalprocedure 1.1: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 7.80 (d, J=8.3 Hz, 2H),7.36 (d, J=8.0 Hz, 2H), 4.35 (d, J=6.3 Hz, 2H), 4.29 (d, J=6.3 Hz, 2H),4.15 (s, 2H), 2.45 (s, 3H), 1.73 (q, J=7.5 Hz, 2H), 0.79 (t, J=7.5 Hz,3H); ¹³C NMR (100 MHz, CDCl₃, δ_(H)) 145.35, 132.72, 130.21, 128.18,71.97, 42.99, 26.26, 21.90, 8.05. ESI-MS: 271.1 (M+H⁺), 293.1 (M+Na⁺).

2-(3-Methyl-3H-diazirin-3-yl)ethyl 4-methylbenzenesulfonate (3w).2-(3-Methyl-3H-diazirin-3-yl)ethanol s6 was synthesized as a crudeproduct from 4-hydroxy-2-butanone s5 by following general procedure 1.6.Compound 3w was synthesized as a colorless oil from crude s6 (500.0 mg,5.0 mmol), TsCl (1.0 g, 5.25 mmol), Et₃N (509.6 mg, 5.5 mmol), and DMAP(600.0 mg, 5.0 mmol) in 12% overall yield from s5 by following generalprocedure 1.1: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 7.81 (d, J=7.5 Hz, 2H),7.38 (d, J=7.5 Hz, 2H), 3.96 (t, J=6.2 Hz, 2H), 2.46 (s, 3H), 1.67 (t,J=6.2 Hz, 2H), 0.99 (s, 3H); ¹³C NMR (100 MHz, CDCl₃, δ_(H)) 145.30,132.83, 130.15, 128.12, 65.46, 34.29, 23.62, 21.82, 19.89. ESI-MS: 255.1(M+H⁺), 277.1 (M+Na⁺).

7-(3-Methyl-3H-diazirin-3-yl)heptyl 4-methylbenzenesulfonate (3x).6-bromo-hexanol s1 (266.0 mg, 1.47 mmol), ethyl acetoacetate s7 (382.6mg, 2.94 mmol), K₂CO₃ (609.5 g, 4.41 mmol), and KI (244.0 mg, 1.47 mmol)were mixed in acetone (25 mL) and DMF (1.5 mL), and the mixture wasrefluxed for 16 h. Most of the acetone was removed under reducedpressure and the residue was worked up with water and diethyl ether. Theextract was dried over Na₂SO₄, concentrated to yield the crude product,which was purified by column chromatography (50:1→1:1 Hexanes-EthylAcetate) to afford s8 (331.8 mg, 98%) as a colorless syrup: ¹H NMR (400MHz, CDCl₃, δ_(H)) 4.14 (q, J=7.1 Hz, 2H), 3.56 (t, J=6.6 Hz, 2H), 3.35(t, J=7.4 Hz, 1H), 2.17 (s, 3H), 1.98 (br s, 1H), 1.88-1.70 (m, 2H),1.57-1.42 (m, 2H), 1.38-1.16 (m, 9H); ¹³C NMR (100 MHz, CDCl₃, δ_(H))203.64, 170.12, 62.89, 61.51, 60.03, 32.73, 29.27, 28.95, 28.24, 27.49,25.61, 14.28. ESI-MS: 231.2 (M+H⁺), 253.2 (M+Na⁺).

Intermediate s7 (339.7 mg, 1.47 mmol) was mixed with 10% aq solution ofKOH (2 mL, 3.57 mmol) and MeOH (2 mL), and the mixture was stirred andheated under reflux for 30 min, and left to stand overnight at roomtemperature. It was then diluted with water, and extracted with diethylether. The ether extract was dried Na₂SO₄, concentrated to yield thecrude product, which was purified by column chromatography (20:1→1:1Hexanes-Ethyl Acetate) to afford s9 (226.4 mg, 97%) as a colorless oil:¹H NMR (400 MHz, CDCl₃, δ_(H)) 3.54 (t, J=6.7 Hz, 2H), 2.35 (t, J=7.4Hz, 2H), 2.29 (br s, 1H), 2.06 (s, 3H), 1.57-1.42 (m, 4H), 1.35-1.15 (m,6H); ¹³C NMR (100 MHz, CDCl₃, δ_(H)) 209.84, 62.85, 43.89, 32.80, 30.02,29.33, 29.25, 25.74, 23.89. ESI-MS: 159.1 (M+H⁺), 181.1 (M+Na⁺).

Compound 3x was synthesized as a colorless oil from crude s9 (1.0 g,6.38 mmol) in 9% overall yield by following general procedures 1.6 and1.1: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 7.69 (d, J=8.3 Hz, 2H), 7.27 (d,J=8.3 Hz, 2H), 3.93 (t, J=6.4 Hz, 2H), 2.36 (s, 3H), 1.61-1.46 (m, 2H),1.31-0.95 (m, 10H), 0.89 (s, 3H); ¹³C NMR (100 MHz, CDCl₃, δ_(H))144.89, 133.28, 130.03, 127.98, 70.77, 34.30, 29.02, 28.85, 28.80,25.32, 24.01, 21.76, 20.03. ESI-MS: 325.2 (M+H⁺), 347.2 (M+Na⁺).

Compounds 7a through 7x can be synthesized using the following generalsynthetic procedure.

General procedure A for the preparation of 7a-7q. To a solution of thephenol 5a-5q (1 equiv.) in DMSO was added NaH (a 60% dispersion inmineral oil, 4-5 equiv.). After the mixture was stirred at 50° C. underargon for 1 h, a solution of 6a (1.05-1.1 equiv.) in DMSO was addeddropwise. After the addition, the temperature was increased to 90° C.,and the solution was stirred under argon for another 3 h. The reactionwas then quenched by the addition of a 50% aqueous NaCl solution, andthe resulting mixture was extracted with CH₂Cl₂. The organic fractionswere dried (Na₂SO₄), filtered, and concentrated under vacuum to yieldthe crude product, which was purified by column chromatography using agradient (1:1 hexanes-EtOAc neat EtOAc) to afford the desired products,which could be further purified by a second column (neat CH₂Cl₂→50:1CH₂Cl₂—CH₃OH) if necessary.

General procedure B for the preparation of 7r-7x. To a slurry of 17a or17b (1 equiv.) in acetonitrile was added 3r-3x (1.3-1.6 equiv.), K₂CO₃(2 equiv.) and 18-Crown-6 (1 equiv.). After the mixture was stirred at40-50° C. under argon for 6-14 h, the solvent was removed under vacuumto yield the crude product, which was purified by column chromatography(neat CH₂Cl₂→50:1 CH₂Cl₂—CH₃OH).

Example 1cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-methyl-3H-1,2,4-triazol-3-one

cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-methyl-3H-1,2,4-triazol-3-one(7a). This compound was synthesized as a colorless oil from 5a (20.1 mg,0.057 mmol), 6a (29.1 mg, 0.060 mmol), and NaH (10.7 mg of a 60%dispersion in mineral oil, 0.27 mmol) in 41% yield by following typicalprocedure A: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 8.20 (br s, 1H), 7.89 (br s,1H), 7.63-7.55 (m, 2H), 7.49-7.36 (m, 3H), 7.25 (dd, J=8.7, 2.4 Hz, 1H),7.05-6.90 (m, 4H), 6.82-6.76 (m, 2H), 4.79 (q, J=14.7 Hz, 2H), 4.40-4.32(m, 1H), 3.94-3.88 (m, 1H), 3.85-3.75 (m, 2H), 3.52 (s, 3H), 3.46 (dd,J=9.7, 6.4 Hz, 1H), 3.38-3.33 (m, 4H), 3.25-3.19 (m, 4H); ¹³C NMR (100MHz, CDCl₃, δ_(C)) 152.82, 152.60, 151.61, 150.89, 146.20, 145.20,136.28, 134.26, 133.34, 131.61, 129.84, 127.48, 125.92, 123.91, 118.69,116.88, 115.47, 107.83, 74.91, 67.83, 67.65, 53.80, 50.80, 49.38, 32.90.MALDI-MS: 663.2 (M+H⁺), 685.2 (M+Na⁺). Purity: 98.5%, t_(R)=6.56 min.

Example 2cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-ethyl-3H-1,2,4-triazol-3-one

cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-ethyl-3H-1,2,4-triazol-3-one(7b). This compound was synthesized as a colorless oil from 5b (18.6 mg,0.051 mmol), 6a (27.7 mg, 0.057 mmol), and NaH (10.0 mg of a 60%dispersion in mineral oil, 0.25 mmol) in 58% yield by following typicalprocedure A: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 8.21 (s, 1H), 7.90 (s, 1H),7.67-7.53 (m, 2H), 7.49-7.37 (m, 3H), 7.25 (dd, J=8.7, 2.3 Hz, 1H),7.09-6.87 (m, 4H), 6.83-6.77 (m, 2H), 4.80 (q, J=14.7 Hz, 2H), 4.46-4.27(m, 1H), 3.99-3.73 (m, 5H), 3.46 (dt, J=23.5, 11.8 Hz, 1H), 3.43-3.32(m, 4H), 3.32-3.16 (m, 4H), 1.46-1.32 (t, J=7.3 Hz, 3H); ¹³C NMR (100MHz, CDCl₃, δ_(C)) 152.86, 152.11, 151.68, 150.84, 146.20, 136.29,134.24, 133.35, 131.66, 129.84, 127.48, 126.02, 123.90, 118.71, 116.89,115.49, 107.85, 74.92, 67.86, 67.67, 53.83, 50.82, 49.40, 40.79, 14.10.MALDI-MS: 677.2 (M+H⁺), 699.2 (M+Na⁺). Purity: >99%, t_(R)=7.04 min.

Example 3cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-propyl-3H-1,2,4-triazol-3-one

cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-propyl-3H-1,2,4-triazol-3-one(7c). This compound was synthesized as a colorless oil from 5c (22.9 mg,0.060 mmol), 6a (32.0 mg, 0.066 mmol), and NaH (10.0 mg of a 60%dispersion in mineral oil, 0.25 mmol) in 53% yield by following typicalprocedure A: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 8.24 (s, 1H), 7.90 (s, 1H),7.65-7.54 (m, 2H), 7.47-7.38 (m, 3H), 7.25 (dd, J=8.4, 2.1 Hz, 1H),7.13-6.95 (m, 4H), 6.85-6.76 (m, 2H), 4.80 (q, J=14.7 Hz, 2H), 4.45-4.28(m, 1H), 3.97-3.73 (m, 5H), 3.60-3.10 (m, 9H), 1.94-1.68 (m, 2H), 0.97(t, J=7.4 Hz, 3H); ¹³C NMR (100 MHz; CDCl₃, δ_(C)) 152.38, 151.69,150.59, 140.03, 136.29, 134.25, 134.12, 133.34, 131.66, 129.83, 127.49,126.09, 123.80, 119.06, 117.02, 115.54, 107.85, 74.87, 67.81, 67.62,53.81, 51.09, 49.23, 47.41, 22.26, 11.34. ESI-MS: 690.2 (M+H⁺), 712.2(M+Na⁺). Purity: 97.4%, t_(R)=7.45 min.

Example 4cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-isopropyl-3H-1,2,4-triazol-3-one

cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-isopropyl-3H-1,2,4-triazol-3-one(7d). This compound was synthesized as a colorless oil from 5d (26.9 mg,0.066 mmol), 6a (35.0 mg, 0.072 mmol), and NaH (10.9 mg of a 60%dispersion in mineral oil, 0.27 mmol) in 50% yield by following typicalprocedure A: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 8.23 (s, 1H), 7.90 (s, 1H),7.67-7.52 (m, 2H), 7.44-7.37 (m, 3H), 7.25 (dd, J=8.3, 2.2 Hz, 1H),7.07-6.89 (m, 4H), 6.84-6.75 (m, 2H), 4.81 (q, J=14.6 Hz, 2H), 4.60-4.50(m, 1H), 4.42-4.30 (m, 1H), 3.96-3.72 (m, 3H), 3.56-3.43 (m, 1H),3.43-3.29 (m, 4H), 3.28-3.17 (m, 4H), 1.41 (d, J=6.7 Hz, 6H); ¹³C NMR(100 MHz, CDCl₃, δ_(c)) 152.82, 152.09, 150.80, 146.23, 136.29, 134.27,134.12, 133.37, 131.66, 129.84, 127.48, 126.06, 123.89, 118.69, 116.89,115.49, 107.84, 74.92, 67.87, 67.68, 53.92, 50.82, 49.44, 47.17, 21.39.ESI-MS: 690.2 (M+H⁺), 712.2 (M+Na⁺). Purity: 94.7%, t_(R)=8.63 min.

Example 5cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-butyl-3H-1,2,4-triazol-3-one

cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-butyl-3H-1,2,4-triazol-3-one(7e). This compound was synthesized as a yellowish oil from 5e (38.8 mg,0.099 mmol), 6a (52.6 mg, 0.11 mmol), and NaH (17.8 mg of a 60%dispersion in mineral oil, 0.45 mmol) in 52% yield by following typicalprocedure A: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 8.21 (s, 1H), 7.89 (s, 1H),7.64-7.52 (m, 2H), 7.46-7.38 (m, 3H), 7.24 (dd, J=8.6, 2.2 Hz, 1H),7.08-6.89 (m, 4H), 6.83-6.77 (m, 2H), 4.79 (q, J=14.7 Hz, 2H), 4.42-4.28(m, 1H), 3.98-3.71 (m, 5H), 3.48 (dd, J=9.6, 6.3 Hz, 1H), 3.55-3.41 (m,4H), 3.40-3.27 (m, 4H), 1.87-1.70 (m, 2H), 1.40 (dq, J=14.7, 7.4 Hz,2H), 0.96 (t, J=7.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃, δ_(C)) 152.83,152.34, 151.55, 150.79, 146.22, 136.26, 134.28, 134.12, 133.34, 131.64,129.83, 127.46, 126.07, 123.77, 118.67, 116.85, 115.51, 107.83, 74.93,67.89, 67.66, 53.84, 50.79, 49.41, 45.55, 30.90, 20.00, 13.87. ESI-MS:705.2 (M+H⁺), 727.2 (M+Na⁺). Purity: >99%, t_(R)=9.89 min.

Example 6cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-isobutyl-3H-1,2,4-triazol-3-one

cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-isobutyl-3H-1,2,4-triazol-3-one(7f). This compound was synthesized as a yellowish oil from 5f (20.0 mg,0.051 mmol), 6a (27.1 mg, 0.058 mmol), and NaH (10.2 mg of a 60%dispersion in mineral oil, 0.26 mmol) in 63% yield by following typicalprocedure A: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 8.22 (s, 1H), 7.89 (s, 1H),7.66-7.51 (m, 2H), 7.48-7.37 (m, 3H), 7.25 (dd, J=8.6, 2.2 Hz, 1H),7.05-6.88 (m, 4H), 6.83-6.76 (m, 2H), 4.80 (q, J=14.7 Hz, 2H), 4.41-4.29(m, 1H), 3.91 (dd, J=8.3, 6.7 Hz, 1H), 3.86-3.72 (m, 2H), 3.65 (d, J=7.3Hz, 2H), 3.47 (dd, J=9.6, 6.4 Hz, 1H), 3.38-3.32 (m, 4H), 3.25-3.19 (m,4H), 2.19 (dt, J=13.7, 6.9 Hz, 1H), 0.97 (d, J=6.7 Hz, 6H); ¹³C NMR (100MHz, CDCl₃) δ_(C)) 152.82, 152.64, 150.79, 146.22, 136.28, 134.28,134.06, 133.34, 131.65, 129.84, 127.47, 126.11, 123.72, 118.68, 116.88,115.48, 107.83, 74.92, 67.86, 67.66, 53.87, 53.04, 50.80, 49.43, 28.46,20.12. ESI-MS: 705.2 (M+H⁺), 727.2 (M+Na⁺). Purity: >99%, t_(R)=9.63min.

Example 7cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-pentyl-3H-1,2,4-triazol-3-one

cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-pentyl-3H-1,2,4-triazol-3-one(7g). This compound was synthesized as a yellowish oil from 5g (23.4 mg,0.057 mmol), 6a (30.0 mg, 0.062 mmol), and NaH (11.4 mg of a 60%dispersion in mineral oil, 0.28 mmol) in 57% yield by following typicalprocedure A: ¹H NMR (400 MHz, CDCl₃, δ_(C)) 8.24 (s, 1H), 7.90 (s, 1H),7.62-7.55 (m, 2H), 7.48-7.38 (m, 3H), 7.25 (dd, J=8.3, 2.1 Hz, 1H),7.15-6.95 (m, 4H), 6.85-6.77 (m, 2H), 4.80 (q, J=14.7 Hz, 2H), 4.42-4.30(m, 1H), 3.99-3.71 (m, 5H), 3.58-3.19 (m, 9H), 1.88-1.70 (m, 2H), 1.35(dd, J=7.2, 3.7 Hz, 4H), 0.90 (dd, J=8.8, 5.0 Hz, 3H); ¹³C NMR (100 MHz,CDCl₃, δ_(C)) 152.32, 150.59, 136.31, 134.22, 134.12, 133.34, 131.67,129.83, 127.50, 123.83, 117.07, 116.68, 115.57, 107.85, 74.86, 67.80,67.60, 53.82, 51.42, 49.13, 45.85, 28.92, 28.58, 22.51, 14.21. ESI-MS:719.3 (M+H⁺), 741.3 (M+Na⁺). Purity: >99%, t_(R)=13.19 min.

Example 8cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(1-methylbutyl)-3H-1,2,4-triazol-3-one

cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(1-methylbutyl)-3H-1,2,4-triazol-3-one(7h). This compound was synthesized as a yellowish oil from 5h (23.4 mg,0.057 mmol), 6a (29.8 mg, 0.062 mmol), and NaH (10.3 mg of a 60%dispersion in mineral oil, 0.26 mmol) in 66% yield by following typicalprocedure A: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 8.26 (s, 1H), 7.91 (s, 1H),7.72-7.53 (m, 2H), 7.48-7.37 (m, 3H), 7.25 (dd, J=8.3, 2.1 Hz, 1H),7.13-6.96 (m, 4H), 6.86-6.79 (m, 2H), 4.81 (q, J=14.7 Hz, 2H), 4.51-4.29(m, 2H), 3.98-3.86 (m, 1H), 3.86-3.71 (m, 2H), 3.58-3.10 (m, 8H),1.93-1.77 (m, 1H), 1.62 (ddt, J=13.6, 9.9, 5.9 Hz, 1H), 1.47-1.18 (m,6H), 0.92 (t, J=7.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃, δ_(C)) 152.10,150.56, 136.29, 134.23, 134.11, 133.34, 131.66, 129.83, 127.49, 123.75,119.06, 117.05, 115.55, 107.84, 74.86, 67.80, 67.61, 53.84, 51.07,49.24, 37.69, 29.93, 19.88, 19.70, 14.00. ESI-MS: 719.3 (M+H⁺),741.3(M+Na⁺). Purity: >99%, t_(R)=9.85 min.

Example 9cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(3-methylbutyl)-3H-1,2,4-triazol-3-one

cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(3-methylbutyl)-3H-1,2,4-triazol-3-one(7i). This compound was synthesized as a yellowish oil from 5i (23.4 mg,0.057 mmol), 6a (30.3 mg, 0.063 mmol), and NaH (11.1 mg of a 60%dispersion in mineral oil, 0.28 mmol) in 63% yield by following typicalprocedure A: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 8.23 (s, 1H), 7.90 (s, 1H),7.67-7.51 (m, 2H), 7.51-7.34 (m, 3H), 7.25 (dd, J=8.4, 2.0 Hz, 1H),7.15-6.97 (m, 4H), 6.88-6.80 (m, 2H), 4.80 (q, J=14.7 Hz, 2H), 4.43-4.27(m, 1H), 3.98-3.70 (m, 5H), 3.56-3.08 (m, 9H), 1.73-1.60 (m, 3H), 0.96(d, J=6.3 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃, δ_(C)) 152.23, 150.60,136.29, 134.24, 134.08, 133.34, 131.66, 129.83, 127.48, 123.76, 119.07,117.03, 115.55, 107.84, 74.86, 67.81, 67.61, 53.83, 51.18, 49.21, 44.19,37.56, 25.81, 22.61. ESI-MS: 719.3 (M+H⁺), 741.3 (M+Na⁺). Purity: >99%,t_(R)=10.10 min.

Example 10cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(1-ethylpropyl)-3H-1,2,4-triazol-3-one

cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(1-ethylpropyl)-3H-1,2,4-triazol-3-one(7j). This compound was synthesized as a yellowish oil from 5j (23.3 mg,0.057 mmol), 6a (30.1 mg, 0.062 mmol), and NaH (10.4 mg of a 60%dispersion in mineral oil, 0.28 mmol) in 63% yield by following typicalprocedure A: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 8.26 (s, 1H), 7.91 (s, 1H),7.69-7.53 (m, 2H), 7.51-7.37 (m, 3H), 7.25 (dd, J=8.4, 2.1 Hz, 1H),7.10-6.93 (m, 4H), 6.85-6.77 (m, 2H), 4.81 (q, J=14.7 Hz, 2H), 4.47-4.29(m, 1H), 4.12-3.99 (m, 1H), 3.99-3.86 (m, 1H), 3.87-3.71 (m, 2H),3.57-3.13 (m, 9H), 1.94-1.62 (m, 4H), 0.88 (t, J=7.4 Hz, 6H); ¹³C NMR(100 MHz, CDCl₃, δ_(C)) 153.05, 150.53, 136.31, 134.22, 133.34, 131.67,129.84, 127.50, 123.74, 119.15, 117.06, 115.57, 107.84, 74.87, 67.81,67.61, 59.06, 53.86, 51.34, 49.22, 27.00, 10.97. ESI-MS: 719.3 (M+H⁺),741.3 (M+Na⁺). Purity: 95.1%, t_(R)=9.17 min.

Example 11cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1.3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(1-cyclohexyl)-3H-1,2,4-triazol-3-one

cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1.3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(1-cyclohexyl)-3H-1,2,4-triazol-3-one(7k). This compound was synthesized as a yellowish oil from 5k (21.8 mg,0.052 mmol), 6a (25.4 mg, 0.055 mmol), and NaH (10.0 mg of a 60%dispersion in mineral oil, 0.25 mmol) in 69% yield by following typicalprocedure A: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 8.20 (s, 1H), 7.88 (s, 1H),7.71-7.51 (m, 2H), 7.47-7.36 (m, 3H), 7.24 (dd, J=8.7, 2.2 Hz, 1H),7.05-6.87 (m, 4H), 6.82-6.74 (m, 2H), 4.79 (q, J=14.7 Hz, 2H), 4.40-4.28(m, 1H), 4.20-4.05 (m, 1H), 3.98-3.71 (m, 3H), 3.46 (dd, J=9.6, 6.3 Hz,1H), 4.43-4.25 (m, 4H), 3.27-3.12 (m, 4H), 1.95-1.63 (m, 6H), 1.49-1.32(m, 2H), 1.30-1.13 (m, 2H); ¹³C NMR (100 MHz, CDCl₃, δ_(C)) 152.80,151.73, 151.60, 150.75, 146.19, 136.26, 134.26, 134.04, 133.33, 131.64,129.83, 127.48, 126.06, 123.89, 118.68, 116.87, 115.45, 107.82, 74.91,67.82, 67.65, 54.31, 5319, 50.80, 49.41, 31.69, 25.65, 25.45. ESI-MS:731.3 (M+H⁺), 753.3 (M+Na⁺). Purity: >99%, t_(R)=7.77 min.

Example 12cis-(2S,4R)-4-[4-[4-[4-[[2-(2/1-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(1-cyclopentylmethyl)-3H-1,2,4-triazol-3-one

cis-(2S,4R)-4-[4-[4-[4-[[2-(2/1-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(1-cyclopentylmethyl)-3H-1,2,4-triazol-3-one(7l). This compound was synthesized as a yellowish oil from 5l (20.0 mg,0.048 mmol), 6a (25.4 mg, 0.052 mmol), and NaH (10.2 mg of a 60%dispersion in mineral oil, 0.26 mmol) in 68% yield by following typicalprocedure A: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 8.21 (s, 1H), 7.89 (s, 1H),7.66-7.53 (m, 2H), 7.51-7.37 (m, 3H), 7.25 (dd, J=8.1, 1.7 Hz, 1H),7.14-6.89 (m, 4H), 6.82-6.72 (m, 2H), 4.80 (q, J=14.7 Hz, 2H), 4.40-4.32(m, 1H), 4.01-3.71 (m, 5H), 3.54-3.15 (m, 9H), 2.43 (dt, J=15.3, 7.6 Hz,1H), 1.95-1.47 (m, 6H), 1.40-1.25 (m, 2H); ¹³C NMR (100 MHz, CDCl₃,δ_(C)) 152.83, 152.52, 151.61, 150.78, 146.21, 136.28, 134.27, 134.00,133.34, 131.65, 129.84, 127.48, 126.12, 123.74, 118.70, 116.89, 115.48,107.84, 74.92, 67.86, 67.66, 53.83, 50.81, 50.53, 49.44, 39.53, 30.36,25.30. ESI-MS: 731.3 (M+H⁺), 753.3 (M+Na⁺). Purity: >99%, t_(R)=7.74min.

Example 13cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(n-octyl)-3H-1,2,4-triazol-3-one

cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(n-octyl)-3H-1,2,4-triazol-3-one(7m). This compound was synthesized as a yellowish oil from 5m (27.4 mg,0.055 mmol), 6a (29.3 mg, 0.060 mmol), and NaH (10.9 mg of a 60%dispersion in mineral oil, 0.27 mmol) in 72% yield by following typicalprocedure A: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 8.21 (s, 1H), 7.90 (s, 1H),7.70-7.51 (m, 2H), 7.50-7.36 (m, 3H), 7.25 (dd, J=8.4, 1.9 Hz, 1H),7.13-6.90 (m, 4H), 6.84-6.73 (m, 2H), 4.80 (q, J=14.7 Hz, 2H), 4.42-4.29(m, 1H), 3.99-3.71 (m, 5H), 3.57-3.12 (m, 9H), 1.85-1.72 (dt, J=14.6,7.4 Hz, 2H), 1.48-1.16 (m, 10H), 0.87 (t, J=6.8 Hz, 3H); ¹³C NMR (100MHz, CDCl₃, δ_(C)) 152.83, 152.33, 151.62, 150.81, 146.22, 136.29,134.27, 134.11, 133.35, 131.66, 129.83, 127.47, 126.08, 123.80, 118.70,116.89, 115.49, 107.85, 74.92, 67.86, 67.67, 53.84, 50.82, 49.43, 45.88,32.00, 29.38, 28.88, 26.80, 22.86, 14.33. ESI-MS: 761.3 (M+H⁺), 783.3(M+Na⁺). Purity: >99%, t_(R)=14.67 min.

Example 14cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(6-phenylhexyl)-3H-1,2,4-triazol-3-one

cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(6-phenylhexyl)-3H-1,2,4-triazol-3-one(7n). This compound was synthesized as a yellowish oil from 5n (25.3 mg,0.051 mmol), 6a (25.9 mg, 0.054 mmol), and NaH (10.9 mg of a 60%dispersion in mineral oil, 0.27 mmol) in 70% yield by following typicalprocedure A: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 8.21 (s, 1H), 7.90 (s, 1H),7.69-7.53 (m, 2H), 7.52-7.35 (m, 3H), 7.33-7.22 (m, 3H), 7.22-7.12 (m,3H), 7.08-6.99 (m, 2H), 6.97-6.89 (m, 2H), 6.83-6.76 (m, 2H), 4.80 (q,J=14.7 Hz, 2H), 4.39-4.32 (m, 1H), 4.01-3.72 (m, 5H), 3.47 (dd, J=9.7,6.4 Hz, 1H), 3.41-3.32 (m, 4H), 3.28-3.18 (m, 4H), 2.67-2.52 (d, J=7.5Hz, 2H), 1.83-1.72 (m, 2H), 1.70-1.56 (m, 2H), 1.46-1.33 (m, 4H); ¹³CNMR (100 MH_(z), CDCl₃, δ_(C)) 152.82, 152.33, 151.62, 150.81, 146.20,142.88, 136.28, 134.27, 134.17, 133.34, 131.66, 129.84, 128.62, 128.46,127.49, 126.04, 125.83, 123.81, 118.70, 116.89, 115.47, 107.84, 74.92,67.83, 67.66, 53.81, 50.81, 49.42, 45.81, 36.07, 31.53, 29.07, 28.83,26.66. ESI-MS: 808.3 (M+H⁺), 830.3 (M+Na⁺). Purity: >99%, t_(R)=12.78min.

Example 15cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(hex-3-ynyl)-3H-1,2,4-triazol-3-one

cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(hex-3-ynyl)-3H-1,2,4-triazol-3-one(7o). This compound was synthesized as a yellowish oil from 5o (25.9 mg,0.062 mmol), 6a (31.6 mg, 0.065 mmol), and NaH (12.8 mg of a 60%dispersion in mineral oil, 0.32 mmol) in 65% yield by following typicalprocedure A: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 8.19 (s, 1H), 7.88 (s, 1H),7.69-7.51 (m, 2H), 7.51-7.33 (m, 3H), 7.24 (dd, J=8.2, 2.0 Hz, 1H),7.06-6.87 (m, 4H), 6.79 (d, J=9.0 Hz, 2H), 4.78 (q, J=14.7 Hz, 2H),4.48-4.25 (m, 1H), 4.06-3.72 (m, 5H), 3.54-3.12 (m, 9H), 2.63 (tt,J=7.3, 2.3 Hz, 2H), 2.13 (qt, J=7.5, 2.3 Hz, 2H), 1.17-0.99 (t, J=7.2Hz, 3H); ¹³C NMR (100 MHz, CDCl₃, δ_(C)) 152.81, 152.25, 151.60, 150.84,146.19, 145.15, 136.26, 134.51, 134.27, 133.33, 131.65, 129.84, 127.48,125.92, 123.83, 118.68, 116.87, 115.46, 107.83, 83.95, 75.41, 74.91,67.83, 67.65, 53.80, 50.79, 49.38, 45.02, 19.26, 14.34, 12.62. ESI-MS:729.2 (M+H⁺), 751.2 (M+Na⁺). Purity: >99%, t_(R)=7.93 min.

Example 16cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(6-azidohexyl)-3H-1,2,4-triazol-3-one

cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(6-azidohexyl)-3H-1,2,4-triazol-3-one(7p). This compound was synthesized as a yellowish oil from 5p (33.1 mg,0.072 mmol), 6a (36.4 mg, 0.075 mmol), and NaH (14.4 mg of a 60%dispersion in mineral oil, 0.36 mmol) in 44% yield by following typicalprocedure A: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 8.19 (s, 1H), 7.87 (s, 1H),7.60 (s, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.44 (d, J=2.1 Hz, 1H), 7.39 (t,J=6.0 Hz, 2H), 7.23 (dd, J=8.4, 2.1 Hz, 1H), 7.00 (d, J=9.0 Hz, 2H),6.93 (d, J=8.8 Hz, 2H), 6.78 (d, J=9.0 Hz, 2H), 4.77 (q, J=14.7 Hz, 2H),4.41-4.25 (m, 1H), 3.94-3.70 (m, 5H), 3.44 (dd, J=9.7, 5.9 Hz, 1H),3.41-3.30 (m, 4H), 3.28-3.16 (m, 6H), 1.88-1.71 (m, 2H), 1.65-1.52 (m,2H), 1.45-1.33 (m, 4H); ¹³C NMR (100 MHz, CDCl₃, δ_(C)) 152.93, 152.32,151.59, 150.76, 136.24, 134.25, 133.32, 131.63, 129.84, 127.47, 126.00,123.77, 118.75, 116.87, 115.47, 107.82, 74.90, 67.81, 67.62, 53.78,51.53, 50.87, 49.33, 45.60, 28.91, 28.72, 26.50, 26.31. ESI-MS: 774.2(M+H⁺), 796.2 (M+Na⁺). Purity: >99%, t_(R)=7.26 min.

Example 17cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(6-(4-benzoylphenoxy)hexyl)-3H-1,2,4-triazol-3-one

cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(6-(4-benzoylphenoxy)hexyl)-3H-1,2,4-triazol-3-one(7q). This compound was synthesized as a yellowish oil from 5q (38.8 mg,0.063 mmol), 6a (34.1 mg, 0.070 mmol), and NaH (12.3 mg of a 60%dispersion in mineral oil, 0.31 mmol) in 74% yield by following typicalprocedure A: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 8.22 (s, 1H), 7.89 (s, 1H),7.84-7.77 (m, 2H), 7.73 (dd, J=8.3, 1.2 Hz, 2H), 7.61 (s, 1H), 7.58-7.52(m, 2H), 7.48-7.42 (m, 3H), 7.39 (d, J=8.9 Hz, 2H), 7.24 (dd, J=8.4, 2.0Hz, 1H), 7.01 (d, J=9.0 Hz, 2H), 6.93 (d, J=8.8 Hz, 4H), 6.79 (d, 7-8.8Hz, 2H), 4.79 (q, J=14.7 Hz, 2H), 4.46-4.25 (m, 1H), 4.02 (t, J=6.4 Hz,2H), 3.96-3.71 (m, 5H), 3.47 (dd, J=9.5, 6.4 Hz, 1H), 3.42-3.28 (m, 4H),3.28-3.12 (m, 4H), 1.83 (dq, J=12.9, 6.6 Hz, 4H), 1.64-1.36 (m, 4H); ¹³CNMR (100 MHz, CDCl₃, δ_(C)) 195.78, 163.01, 152.82, 152.36, 151.68,150.82, 146.21, 138.54, 136.26, 134.24, 133.33, 132.77, 132.05, 131.64,130.11, 129.93, 129.84, 128.39, 127.47, 125.96, 123.77, 118.67, 116.84,115.49, 114.23, 107.82, 74.92, 68.26, 67.86, 67.64, 53.86, 50.78, 49.37,45.66, 29.14, 28.76, 26.46, 25.81. ESI-MS: 929.3 (M+H⁺), 951.3 (M+Na⁺).Purity: >99%, t_(R)=15.68 min.

Example 18cis-(2R,4S)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(pent-4-ynyl)-3H-1,2,4-triazol-3-one

cis-(2R,4S)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(pent-4-ynyl)-3H-1,2,4-triazol-3-one(7r). This compound was synthesized as a yellowish oil from 17b (25.6mg, 0.039 mmol), 3r (14.1 mg, 0.059 mmol), K₂CO₃ (10.9 mg, 0.079 mmol),and 18-Crown-6 (10.4 mg, 0.039 mmol) in 40% yield by following typicalprocedure B: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 8.22 (s, 1H), 7.90 (s, 1H),7.62 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.48 (d, J=2.1 Hz, 1H), 7.42 (dd,J=7.1, 5.1 Hz, 2H), 7.25 (dd, J=8.7, 2.3 Hz, 1H), 7.03 (d, J=9.1 Hz,2H), 6.94 (d, J=9.0 Hz, 2H), 6.80 (d, J=9.0 Hz, 2H), 4.81 (q, J=14.7 Hz,2H), 4.41-4.33 (m, 1H), 4.04-3.88 (m, 3H), 3.87-3.74 (m, 2H), 3.49 (dd,J=9.7, 6.4 Hz, 1H), 3.42-3.34 (m, 4H), 3.27-3.19 (m, 4H), 2.32 (td,J=7.0, 2.6 Hz, 2H), 2.11-1.96 (m, 3H); ¹³C NMR (100 MHz, CDCl₃, δ_(C))152.84, 152.38, 151.68, 150.86, 146.24, 136.29, 134.35, 133.35, 131.66,129.83, 127.47, 125.95, 123.79, 118.69, 116.86, 115.51, 107.85, 83.19,74.93, 69.28, 67.89, 67.67, 53.87, 50.80, 49.40, 44.74, 27.71, 16.16.ESI-MS: 715.2 (M+H⁺), 737.2 (M+Na⁺). Purity: >99%, t_(R)=7.35 min.

Example 19cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-((E)-hex-3-enyl)-3H-1,2,4-triazol-3-one

cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-((E)-hex-3-enyl)-3H-1,2,4-triazol-3-one(7s). This compound was synthesized as a yellowish oil from 17a (19.8mg, 0.031 mmol), 3s (12.3 mg, 0.048 mmol), K₂CO₃ (8.4 mg, 0.061 mmol),and 18-Crown-6 (8.1 mg, 0.031 mmol) in 55% yield by following typicalprocedure B: ¹H NMR (400 MHz, CDCl₃, F_(H)) 8.23 (s, 1H), 7.90 (s, 1H),7.61-7.55 (m, 2H), 7.51-7.37 (m, 3H), 7.25 (dd, J=8.4, 1.8 Hz, 1H), 7.03(d, J=9.0 Hz, 2H), 6.95 (d, J=8.9 Hz, 2H), 6.81 (d, J=8.9 Hz, 2H), 5.50(dtt, J=15.3, 6.3, 1.3 Hz, 1H), 5.31-5.15 (m, 1H), 4.84 (q, J=14.7 Hz,2H), 4.49-4.32 (m, 1H), 3.92-3.73 (m, 6H), 3.52 (dd, J=9.7, 6.5 Hz, 1H),3.41-3.33 (m, 4H), 3.26-3.17 (m, 4H), 2.43 (q, J—7.0 Hz, 2H), 2.08-1.92(m, 2H), 0.92 (t, J=7.5 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃, δ_(C)) 152.83,152.36, 151.66, 150.85, 146.21, 136.28, 134.77, 134.29, 133.34, 131.67,129.84, 127.49, 126.00, 124.52, 123.81, 118.70, 116.88, 115.48, 107.85,74.92, 67.83, 67.66, 53.82, 50.82, 49.42, 45.57, 25.90, 21.82, 14.03.ESI-MS: 731.2 (M+H⁺), 753.2 (M+Na⁺). Purity: 95.3%, t_(R)=9.15 min.

Example 20cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-13-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-((Z)-hex-3-enyl)-3H-1,2,4-triazol-3-one

cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-13-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-((Z)-hex-3-enyl)-3H-1,2,4-triazol-3-one(7t). This compound was synthesized as a yellowish oil from 17a (18.7mg, 0.029 mmol), 3t (11.0 mg, 0.043 mmol), K₂CO₃ (8.0 mg, 0.058 mmol),and 18-Crown-6 (7.6 mg, 0.029 mmol) in 70% yield by following typicalprocedure B: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 8.21 (s, 1H), 7.89 (s, 1H),7.62-7.55 (m, 2H), 7.50-7.36 (m, 3H), 7.25 (dd, J=8.5, 1.7 Hz, 1H), 7.02(d, J=9.0 Hz, 2H), 6.94 (d, J=8.9 Hz, 2H), 6.80 (d, J=8.9 Hz, 2H), 5.50(dt, J=10.7, 7.2 Hz, 1H), 5.44-5.31 (m, 1H), 4.85 (q, J=14.7 Hz, 2H),4.48-4.30 (m, 1H), 3.95-3.75 (m, 6H), 3.49 (dd, J=9.9, 6.3 Hz, 1H),3.42-3.34 (m, 4H), 3.27-3.19 (m, 4H), 2.54 (q, J=7.0 Hz, 2H), 2.12-1.97(m, 2H), 0.93 (t, J=7.5 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃, δ_(C)) 152.83,152.34, 151.64, 150.84, 146.19, 136.29, 134.93, 134.21, 133.34, 131.66,129.84, 127.49, 126.01, 124.33, 123.83, 118.71, 116.89, 115.47, 107.84,74.92, 67.83, 67.66, 53.82, 50.82, 49.42, 45.60, 26.89, 20.80, 14.47.ESI-MS: 731.2 (M+H⁺), 753.2 (M+Na⁺). Purity: 95.0%, t_(R)=8.91 min.

Example 21cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-]piperazinyl]phenyl]-2,4-dihydro-2-(5-cyanopentyl)-3H-1,2,4-triazol-3-one

cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-]piperazinyl]phenyl]-2,4-dihydro-2-(5-cyanopentyl)-3H-1,2,4-triazol-3-one(7u). This compound was synthesized as a yellowish oil from 17a (40.0mg, 0.062 mmol), 3u (16.3 mg, 0.092 mmol), K₂CO₃ (17.1 mg, 0.124 mmol),and 18-Crown-6 (16.3 mg, 0.062 mmol) in 41% yield by following typicalprocedure B: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 8.25 (s, 1H), 7.90 (s, 1H),7.65-7.55 (m, 2H), 7.48 (d, J=1.7 Hz, 1H), 7.41 (d, J=8.8 Hz, 2H), 7.25(dd, J=8.4, 2.0 Hz, 1H), 7.03 (d, J=8.9 Hz, 2H), 6.94 (d, J=8.7 Hz, 2H),6.81 (d, J=8.7 Hz, 2H), 4.81 (q, J=14.7 Hz, 2H), 4.50-4.25 (m, 1H),4.05-3.71 (m, 5H), 3.49 (t, J=7.8 Hz, 1H), 3.43-3.33 (m, 4H), 3.29-3.20(m, 4H), 2.37 (t, J=7.1 Hz, 2H), 1.93-1.81 (m, 2H), 1.80-1.69 (m, 2H),1.60-1.49 (m, 2H); ¹³C NMR (100 MHz, CDCl₃, δ_(C)) 152.85, 152.44,150.91, 146.24, 136.30, 134.42, 134.28, 133.35, 131.66, 129.84, 127.48,125.87, 123.87, 118.70, 116.87, 115.51, 107.83, 74.93, 67.89, 67.67,53.95, 50.80, 49.39, 45.19, 28.01, 25.80, 25.15, 17.31. ESI-MS: 744.2(M+H⁺), 766.2 (M+Na⁺). Purity: 94.9%, t_(R)=5.36 min.

Example 22cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-((3-ethyloxetan-3-yl)methyl)-3H-1,2,4-triazol-3-one

cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-((3-ethyloxetan-3-yl)methyl)-3H-1,2,4-triazol-3-one(7v). This compound was synthesized as a yellowish oil from 17a (30.0mg, 0.046 mmol), 3v (18.7 mg, 0.069 mmol), K₂CO₃ (12.8 mg, 0.092 mmol),and 18-Crown-6 (12.2 mg, 0.046 mmol) in 40% yield by following typicalprocedure B: ¹H NMR (400 MHz, CDCl₃, δ_(H)) 8.21 (s, 1H), 7.90 (s, 1H),7.72-7.52 (m, 2H), 7.52-7.36 (m, 3H), 7.25 (dd, J=8.5, 2.2 Hz, 1H),7.13-6.72 (m, 6H), 4.91-4.69 (m, 4H), 4.45 (d, J=6.3 Hz, 2H), 4.41-4.32(m, 1H), 4.07 (s, 2H), 3.92 (dd, J=8.3, 6.7 Hz, 1H), 3.87-3.73 (m, 2H),3.54-3.44 (m, 1H), 3.43-3.32 (m 4H), 3.30-3.23 (m, 4H), 1.74 (dd,J=14.9, 7.4 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃,δ_(C)) 152.84, 151.60, 150.92, 146.20, 145.18, 136.28, 134.63, 134.27,133.34, 131.65, 129.84, 127.48, 125.80, 123.79, 118.70, 116.87, 115.49,107.84, 78.88, 74.92, 67.86, 67.66, 53.82, 50.80, 49.38, 49.26, 44.25,27.57, 8.34. ESI-MS: 747.3 (M+H⁺), 769.3 (M+Na⁺). Purity: 94.6%,t_(R)=5.85 min.

Example 23cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(2-(3-methyl-3H-diazirin-3-yl)ethyl)-3H-1,2,4-triazol-3-one

cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(2-(3-methyl-3H-diazirin-3-yl)ethyl)-3H-1,2,4-triazol-3-one(7w). This compound was synthesized as a yellowish oil from 17a (20.2mg, 0.031 mmol), 3w (10.3 mg, 0.040 mmol), K₂CO₃ (8.6 mg, 0.062 mmol),and 18-Crown-6 (8.2 mg, 0.031 mmol) in 55% yield by following typicalprocedure B: ¹H NMR (400 MHz, CDCl₃, δH) 8.24 (s, 1H), 7.90 (s, 1H),7.64 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.48 (d, J=2.1 Hz, 1H), 7.45-7.39(m, 2H), 7.26 (dd, J=8.6, 2.1 Hz, 1H), 7.04 (d, J=9.0 Hz, 2H), 6.94 (d,J=8.6 Hz, 2H), 6.81 (d, J=8.7 Hz, 2H), 4.81 (q, J=14.7 Hz, 2H),4.43-4.31 (m, 1H), 3.98-3.85 (m, 3H), 3.85-3.75 (m, 2H), 3.49 (dd,J=9.4, 6.4 Hz, 1H), 3.40-3.34 (m, 4H), 3.28-3.20 (m, 4H), 1.81 (t, J=7.1Hz, 2H), 1.10 (s, 3H); ¹³C NMR (100 MHz, CDCl₃, δ_(C)) 152.84, 152.36,150.95, 146.23, 136.29, 134.68, 134.28, 133.35, 131.66, 129.84, 127.47,125.85, 123.95, 118.70, 116.87, 115.51, 107.84, 74.93, 67.88, 67.67,53.90, 50.80, 49.39, 41.08, 33.91, 24.16, 19.57. ESI-MS: 731.2 (M+H⁺),753.2 (M+Na⁺). Purity: 93.7%, t_(R)=9.84 min.

Example 24cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(7-(3-methyl-3H-diazirin-3-yl)heptyl)-3H-1,2,4-triazol-3-one

cis-(2S,4R)-4-[4-[4-[4-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1piperazinyl]phenyl]-2,4-dihydro-2-(7-(3-methyl-3H-diazirin-3-yl)heptyl)-3H-1,2,4-triazol-3-one(7x). This compound was synthesized as a yellowish oil from 17a (21.9mg, 0.034 mmol), 3x (16.4 mg, 0.051 mmol), K₂CO₃ (9.3 mg, 0.067 mmol),and 18-Crown-6 (8.9 mg, 0.034 mmol) in 57% yield by following typicalprocedure B: ¹H NMR (400 MHz, CDCl₃, δH) 8.22 (s, 1H), 7.90 (s, 1H),7.64-7.52 (m, 2H), 7.52-7.33 (m, 3H), 7.25 (dd, J=8.5, 1.9 Hz, 1H),7.05-6.88 (m, 4H), 6.80 (d, J=8.6 Hz, 2H), 4.80 (q, J=14.7 Hz, 2H),4.46-4.27 (m, 1H), 3.99-3.71 (m, 5H), 3.57-3.42 (m, 1H), 3.43-3.28 (m,4H), 3.28-3.15 (m, 4H), 1.78 (dt, J=14.7, 7.3 Hz, 2H), 1.44-1.08 (m,10H), 1.02-0.92 (m, 3H); ¹³C NMR (100 MHz, CDCl₃, δ_(C)) 152.84, 152.33,150.81, 146.19, 136.28, 134.27, 134.16, 133.34, 131.65, 129.83, 127.47,126.04, 123.80, 118.70, 116.88, 115.49, 107.84, 74.92, 67.86, 67.66,53.86, 50.81, 49.41, 45.76, 34.47, 29.21, 29.15, 28.78, 26.59, 24.15,20.11. ESI-MS: 801.3 (M+H⁺), 823.3 (M+Na⁺). Purity: 92.9%, t_(R)=10.84min.

Example 254-(4-(4-(4-(((2R,4S)-2-((1H-1,2,4-triazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one(17a)

Compounds 17a and 17b were prepared according to Scheme 3 (and asdescribed in J. Heeres, L. J. J. B., and J. Van Cutsem (1984).“Antimycotic azoles. 7. Synthesis and antifungal properties of a seriesof novel triazol-3-ones.” J. Med. Chem. 27(4): 894-900).

1-(2-Fluoro-4-nitrophenyl)-4-(4-methoxyphenyl)piperazine (3)

To a suspension containing 0.16 g of 1,2-difluoro-4-nitrobenzene (2) and0.28 mL of N-diisopropyl ethylamine (DIPEA) in 4 mL acetonitrile, 0.19of 1-(4-methoxyphenyl)piperazine (1) was added. The reaction mixture wasstirred at room temperature for over night (12 h). The reaction mixturewas filtered to get the yellowish solid. Then the collected solid waswashed with hexane to get nitro compound 3 (0.25 g, 75%). ¹H NMR (400MHz, CDCl₃, δ_(H)): 8.01 (dd, J=8.8, 2.4 Hz, 1H), 7.93 (dd, J=12.8, 2.4Hz, 1H), 6.99-6.97 (m, 3H), 6.89-6.87 (m, 2H), 3.79 (s, 3H), 3.47 (bs,4H), 3.26 (d, J=4.8 Hz, 4H). ¹³C NMR (100 MHz, CDCl₃, δ_(C)): 154.4,151.9, 121.0, 118.9, 117.3, 114.6, 112.8, 112.5, 55.6, 51.0, 49.6.

3-Fluoro-4-(4-(4-methoxyphenyl)piperazin-1-yl)aniline (4)

To a stirred suspension of compound 3 (0.2 g, 0.6 mmol) and palladiumcatalyst (10% Pd on carbon 0.04 g) in ethanol (6 mL), hydrazinemonohydrate (0.29 mL, 5.7 mmol) was added slowly and the reactionmixture was heated to reflux for 4 h. After cooling to room temperature,the reaction mixture was filtered and the filtrate was concentrated toobtain amine 4 (0.17 g, 93%).

Phenyl (3-fluoro-4-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)carbamate(5)

To a solution of 4 (0.32 g, 1 mmol) and pyridine (0.12 mL, 1.5 mmol) inacetonitrile (4 mL, 0.25M), phenyl chloroformate (0.16 mL, 1.2 mmol) wasadded at 0° C. and the reaction mixture was stirred at room temperaturefor overnight. Then water was added and the mixture was stirred for 30min. The precipitated white solid was filtered and the solid was washedwith acetonitrile and then dried under vacuum to obtain compound 5 (0.35g, 83%).

N-(3-fluoro-4-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)hydrazinecarboxamide(6)

To a solution containing 5 (0.3 g, 0.7 mmol) and hydrazine monohydride(0.19 mL, 3.7 mmol) in 1,4-dioxane. The reaction mixture was stirred andheated to reflux for 4 h. After cooling to room temperature water wasadded and the mixture was stirred for 30 min. The precipitated solid wasfiltered and the solid was washed with acetonitrile and then dried undervacuum to obtain the hydrazinecarboxamide intermediate 6 (0.2 g, 82%).

4-(3-fluoro-4-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one(7)

The mixture of hydrazinecarboxamide 7 (0.15 g, 0.4 mmol) and formamidineacetate (0.27 g, 2.8 mmol) in 1-propanol (4 mL, 0.1M) was heated toreflux for 3 h. After cooling to room temperature, the reaction mixturewas diluted with water. The solid was filtered, washed with 50% aqueous1-propanol, and then dried under vacuum to obtain 7 (0.11 g, 80%) as anoff-white solid.

1-(sec-butyl)-4-(3-fluoro-4-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one(8)

To a suspension of triazolone 7 (0.11 g, 0.3 mmol) in dimethylsulfoxide(4 mL) was added K₂CO₃ (0.08 g, 0.6 mmol). The resulting mixture wasstirred at room temperature for 1 h. After the addition of 2-bromobutane (0.05 mL, 0.45 mmol), the temperature increased to 80° C. forovernight. After cooling to room temperature, the reaction mixture wasdiluted with water and extracted with dichlormethane. The combinedorganic layer was dried over Na₂SO₄, filtered, and concentrated to yieldthe crude product, which was purified by column chromatography to obtaintriazolone 8 (0.11 g, 87%). ¹H NMR (400 MHz, CDCl₃, δ_(H)): 7.64 (s,1H), 7.37 (dd, J=13.0, 2.2 Hz, 1H), 7.26-7.24 (m, 1H), 7.04 (t, J=8.8Hz, 1H), 6.99-6.97 (m, 2H), 6.88-6.84 (m, 2H), 4.31-4.26 (m, 1H), 3.77(s, 3H), 3.26 (bs, 8H), 1.86-1.81 (m, 1H), 1.73-1.71 (m, 1H), 1.38 (d,J=6.8 Hz, 3H), 0.89 (t, J=7.4 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃, δ_(C)):154.6, 154.2, 151.6, 139.4, 133.3, 128.4, 119.4, 118.7, 118.0, 114.5,111.0, 110.8, 55.6, 52.8, 51.0, 50.5, 28.4, 19.3, 10.8.

1-(sec-butyl)-4-(3-fluoro-4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one(9)

Triazolone 8 (0.1 g, 0.23 mmol) was added to aqueous HBr (48%, 1.9 mL)The reaction was heated to 120° C. and refluxed overnight. The reactionmixture was cooled to room temperature and the solution was neutralizedwith saturated Na₂CO₃ and extracted with dichloromethane (DCM). Thecombined organic layer was dried (Na₂SO₄), filtered, and concentrated toyield the product, which was purified by column chromatography to obtaincompound 9 (0.08 g, 83%). ¹H NMR (400 MHz, CDCl₃, δ_(H)): 7.57 (s, 1H),7.24 (dd, J=10.2, 2.0 Hz, 1H), 7.15 (dd, J=6.8, 1.6 Hz, 1H), 6.92 (t,J=7.0 Hz, 1H), 6.79 (d, J=6.8 Hz, 2H), 6.67 (d, J=7.2 Hz, 2H), 4.24-4.20(m, 1H), 3.17-3.16 (m, 8H), 1.82-1.77 (m, 1H), 1.66-1.63 (m, 1H), 1.32(d, J=5.6 Hz, 3H), 0.82 (t, J=5.8 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃,δ_(C)): 156.3, 154.3, 150.8, 144.9, 139.7, 133.6, 127.8, 119.4, 118.9,116.0, 111.4, 53.1, 51.2, 50.5, 28.4, 19.3, 10.8.

General Experimental Procedure for the Preparation of 12 or 13:

To a solution of 9 in DMSO was added NaH (60% dispersion in mineral oil)and the temperature increased to 50° C. under argon for 1 h. A solutionof 10 or 11 in DMSO was added drop wise and the temperature wasincreased to 70° C. and stirred for 3 h. After cooling to roomtemperature, the reaction mixture was quenched with 50% aqueous NaClsolution and the reaction mixture was diluted in water. The aqueoussolution was extracted with DCM, the organic layer was dried overNa₂SO₄, which was purified by column chromatography.

General Experimental Procedure for the Preparation of 18-21:

The mixture of compounds 14 or 15, 16 or 17, Pd₂(dba)₃, t-BuONa, andrac-BINAP in dry toluene was stirred overnight at 80° C. under argonatmosphere. After cooling to room temperature, the reaction mixture wasdiluted in water and the resulting solid was filtered. The aqueoussolution was extracted with DCM, the organic layer was dried overNa₂SO₄, which was purified by column chromatography.

The synthetic methods for the following compounds 22-25 were similar tothe synthesis of compound 4.

The synthetic methods for the following compounds 26-29 were similar tothe synthesis of compound 5.

The synthetic methods for the following compounds 30-33 were similar tothe synthesis of compound 6.

The synthetic methods for the following compounds 34-37 were similar tothe synthesis of compound 7.

The synthetic methods for the following compounds 38-41 were similar tothe synthesis of compound 8.

The synthetic methods for the following compounds 42-45 were similar tothe synthesis of compound 9.

The synthetic methods for the following compounds 46a-49b and 46a-49bwere similar to the synthesis of compound 12 or 13.

The biological activity of the compounds in Examples 1-24 is illustratedin the following assays. The other compounds listed above, which havenot yet been made and/or tested, are predicted to have activity in theseassays as well.

Biological Activity Assay

HUVEC Culture and Proliferation Assays

Pooled HUVEC (Lonza) were grown in EGM-2 bullet kit media (Lonza) andused at passage eight or lower. The proliferation assays were conductedas previously described (Nacev, B.; Low, W. K.; Huang, Z.; Su, T.; Su,Z.; Alkuraya, H.; Kasuga, D.; Sun, W.; Trager, M.; Braun, M.; Fischer,G.; Zhang, K.; Liu, J. O., A calcineurin-independent mechanism ofangiogenesis inhibition by a non-immunosuppressive Cyclosporin A analog.J. Pharmacol. Exp. Ther. 2011, DOI:10.1124/jpet.111.18085).

TABLE 5 Itraconazole Analogs and their Activity in HUVEC Proliferation(IC₅₀) No. Compound Structure IC₅₀ (nM) 1 Itraconazole (Standard)

180.5 2 Itraconazole A (2S, 4R, 2′S)

167.3 3 Itraconazole C (2S, 4R, 2′R)

151.9 4 13

419.0 5 12

235.9 6 46b

235.9 7 46a

154.9 8 47a

154.8

VEGFR2 Glycosylation

HUVEC were seeded at 5×10⁴ per well of a 6-well plate in 3 mL of media.After an overnight recovery, the media was replaced with 2 mL freshmedia and the analogs were added from 200× stocks in DMSO. Following a24-h incubation, the media was aspirated and 2×SDS sample buffer wasadded to the cells which were incubated on ice for 10 min and thenboiled for 10 min. The lysate was then subjected to 6% SDS-PAGE andtransferred to PVDF (Bio-Rad) membranes which were subsequently blockedin 5% BSA (Sigma) in TBS-T (10 mM Tris pH 8.0, 150 mM NaCl, 0.05 Tween20 [Sigma]) and then incubated with 1% anti-VEGFR2 in 1% BSA in TBS-T(cell signaling #2749). Following three washes in TBS-T, the membranewas incubated with anti-rabbit horseradish peroxidase conjugated IgG (GEHealthcare) (1:5000-1:10000 dilution) in 1% BSA in TBS-T. The membraneswere washed three times in TBS-T, incubated for 1-5 minutes with ECLsubstrate (Immobilon Wester, Milipore) and visualized (Kodak ImageStaion 440 CF).

Medulloblastoma Culture

MB cultures were derived from mouse Ptch^(−/+); p53^(−/−) MB grown ashind-flank allografts in nude mice (Harlan). Briefly, tumors weremechanically disrupted and made into single cell suspensions by twopassages through a 70 μm nylon filter. Cells were pelleted bycentrifugation and resuspended in PBS pH 7.4 twice. The cell suspensionwas then subjected to centrifugation at 1000×g for 25 min over a ficollgradient. The viable cell layer formed at the ficoll boundary was thencollected, suspended in PBS, and pelleted by centrifugation. Theresulting pellet was then suspended and cultured as “neurospheres” inNeurobasal Media-A supplemented with retinoic acid deficient B-27extract (NBMedia). Cells were cultured for three passages, withneurospheres disaggregated using Accumax (Innovative Cell Technologies)between passages. Prior to assaying, CD15 expression was confirmed byflow cytometric analysis. Inhibition of proliferation and Glitranscription was also confirmed in response to HhAntag and GDC-0449(FIG. 9).

Medulloblastoma Proliferation Assay

Cultured MB neurospheres were disaggregated as described and 1×10⁴ cellswere seeded into wells of a 96-well assay plate in NBMedia and exposedto multiple analogue concentrations. Relative cell numbers following a96-h incubation were quantified by CellTiter 96® AQ_(ueous) One SolutionCell Proliferation Assay (Promega) per manufacturer's recommendationsusing a SpectraMax M2e spectrophotometer and SoftMax Pro software(Molecular Devices). Data was analyzed using Prism5 (GraphPad Software)and IC₅₀ and IC₉₀ values were determined from dose-response curvesfitted to mean corrected absorbance normalized to control treatment.

Quantification of Gli1 Transcript by TaqMan Analysis.

MB neurospheres were cultured in NBMedia to confluence in 25 cm³ cultureflasks and exposed for 24 h to analogs at the experimentally determinedIC₉₀ for proliferation. Following drug exposure, cells were washed inPBS and pelleted by centrifugation at 300×g. Cell pellets were lysed inTrizol reagent (Invitrogen). Total RNA was separated and collected inthe aqueous phase following centrifugation of lysate in the presence ofchloroform. Total RNA was ethanol precipitated and purified over RNeasyMini Kit (Qiagen) filter columns per manufacturer's recommendations.Transcript levels were quantified using gene-specific TaqManprimer/probe sets and the StepOne Plus Real-Time PCR system (AppliedBiosystems) on cDNA reverse transcribed using the QuantiTect ReverseTranscription Kit (Qiagen) per manufacturers' recommendations. Resultswere quantified using StepOne Plus software v2.1 (Applied Biosystems)and were expressed as fold induction relative to control samples usingthe Δ ΔCt (2^(−ΔΔct)) method with actin as an internal control. Theprimer/probe set (Applied Biosystems) for TaqMan PCR for mouse Gli-1 wasMm00494645_ml, and for mouse actin was Mm00607939_s1. Fold inductionvalues for Gli1 transcript at the IC₉₀ for MB proliferation were scoredon a three-point semi-quantitative scale as follows: ++, ≦0.15; +, 0.16to 0.44; −, ≧0.45.

Although the invention has been described with reference to the aboveexamples, it will be understood that modifications and variations areencompassed within the spirit and scope of the invention. Accordingly,the invention is limited only by the following claims.

What is claimed is:
 1. A compound of structural Formula (I):

or an optically pure stereoisomer or pharmaceutically acceptable saltthereof, wherein: X and Y are each independently CH, or N; A is CR⁶ orN; B is CR⁷ or N; W is CR⁸ or N; V is CR⁹ or N; Z is CR¹⁰ or N; Q is Oor CH₂; each R², R³, R⁴, and R⁵ are independently chosen from the groupconsisting of alkoxy, alkyl, amino, halogen, hydroxy, haloalkyl,perhaloalkyl, perhaloalkoxy, nitro, and cyano; R⁶, R⁷, R⁸, and R⁹ areeach independently chosen from the group consisting of hydrogen, alkoxy,alkyl, amino, halogen, hydroxy, haloalkyl, perhaloalkyl, perhaloalkoxy,nitro, and cyano; T is —OR¹¹ or hydrogen; R¹¹ is hydrogen or alkyl; G is—(CH₂)_(n) or G and R¹¹ may optionally be joined together to form adioxolane; R¹ and R¹⁰ are each independently hydrogen or alkyl; n is aninteger between 0 and 2; p and t are each independently an integerbetween 0 and 2; q and m are each independently an integer between 0 and4; D is chosen from the group consisting of

U is O or S; R¹² and R¹³ are each independently chosen from the groupconsisting of hydrogen and alkyl; and R¹⁴ is chosen from the groupconsisting of hydrogen, alkyl, arylalkyl, alkoxyalkyl, arylalkoxy,alkynylalkyl, alkenylalkyl, cycloalkyl, cyanoalkyl, cycloalkylalkyl,heteroalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, andheterocycloalkylalkyl.
 2. The compound of claim 1, wherein: X and Z areN; Y is CH; A is CR⁶; B is CR⁷; W is CR⁸; V is CR⁹; D is

p, t, and q are each independently 0; m is 2; and R¹, R⁶, R⁷, R⁸, and R⁹are each independently hydrogen.
 3. The compound of claim 2, wherein thecompound is of structural Formula (II):


4. The compound of claim 3, wherein Q is CH₂.
 5. The compound of claim4, wherein T is hydrogen.
 6. The compound of claim 4, wherein: T isOR¹¹; and R¹¹ is hydrogen.
 7. The compound of claim 3, wherein Q is O.8. The compound of claim 7, wherein T is hydrogen.
 9. The compound ofclaim 7, wherein: T is OR11; and R11 is hydrogen.
 10. The compound ofclaim 2, wherein the compound is of structural Formula (III):

wherein: R¹⁴ is chosen from the group consisting of hydrogen, alkyl,arylalkyl, alkoxyalkyl, arylalkoxy, alkynylalkyl, alkenylalkyl,cycloalkyl, cyanoalkyl, cycloalkylalkyl, and heterocycloalkylalkyl. 11.The compound of claim 1, wherein the compound is of structural Formula(IV):


12. The compound of claim 11, wherein: m is 2; and each R² isindependently chlorine.
 13. The compound of claim 12, wherein R¹⁴ is


14. The compound of claim 13, wherein: W is CR8; and V is CR9.
 15. Thecompound of claim 14, wherein p is
 0. 16. The compound of claim 15,wherein: each R4 is independently alkyl; and q is 0, 1, or
 2. 17. Thecompound of claim 16, wherein: each R5 is independently halogen; and tis 0, 1, or
 2. 18. The compound of claim 17, wherein A is CR⁶.
 19. Thecompound of claim 18, wherein B is CR⁷.
 20. The compound of claim 18,wherein B is N.